Ocular gene therapy targeting retinal angiogenesis and vascular leakage: translational and clinical evidence from a systematic review and meta-analysis - Kai-Yang Chen; Hoi-Chun Chan; Chi-Ming Chan (Angiogenesis, 2026)
Introduction Retinal diseases driven by pathological angiogenesis and vascular leakage, including neovascular age-related macular degeneration and diabetic retinopathy, impose substantial visual and treatment burdens because current anti-vascular endothelial growth factor (anti-VEGF) therapy requires repeated intravitreal administration. Ocular gene therapy can provide durable intraocular expression of therapeutic proteins and sustained pathway-level disease control. Methods This systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, Scopus, Web of Science, ScienceDirect, and the Cochrane Library were searched from inception to April 21, 2026. Eligible studies included preclinical, in vitro, and clinical investigations of gene-based interventions targeting retinal angiogenesis, vascular permeability, or related anatomical and treatment-burden outcomes. Random-effects meta-analyses were performed using standardized mean differences (SMDs), mean differences (MDs), and logit event rates. Results Twenty-five studies were included. Preclinical gene therapy significantly reduced pathological neovascularization, with a pooled standardized mean difference (SMD) of −1.16 (95% confidence interval [CI], −1.48 to −0.84; p < 0.001) and negligible heterogeneity (I² = 0%). Vascular leakage was also significantly reduced across preclinical experimental studies, with a pooled mean difference (MD) of 0.215 (95% CI, 0.178–0.251; p < 0.001; I 2 = 0%) after directional harmonization. In clinical cohorts, ocular gene therapy significantly reduced central subfield thickness (CST) by −55.30 μm (95% CI, −72.58 to −38.03; p < 0.001) and was associated with reduced anti-vascular endothelial growth factor (anti-VEGF) treatment burden, with a pooled logit event rate of 0.62 (95% CI, 0.20–1.04; p = 0.0039), corresponding to a pooled proportion of approximately 65% of participants meeting study-specific criteria for reduced supplemental anti-VEGF use. Conclusion Ocular gene therapy shows strong preclinical anti-angiogenic and anti-permeability effects, with emerging clinical evidence of anatomical improvement and reduced anti-VEGF treatment burden in neovascular retinal disease cohorts. Larger disease-specific randomized trials are required to confirm long-term efficacy, safety, and patient selection.

Evaluating the endothelial glycocalyx from bench to bedside: a translational framework for microvascular assessment - Hiroyuki Tomita; Akio Suzuki; Hideshi Okada (Angiogenesis, 2026)

Integrin inhibition differentially remodels vascular networks in lung metastases driven by vessel co-option or angiogenesis - Laura Marcos-Zazo; Iván Carrera-Aguado; Jesús Gómez-Escudero; Patricia Berlana-Galán; Irene Torre-Cea; Elena Guerra-Paes; Celia Redondo-Gonzalez; Juan Sánchez-Mateos; Daniel Cáceres-Calle; Óscar Maiques; Miguel Pericacho; Susana Fraile; et al. (Angiogenesis, 2026)
Tumor progression depends on an adequate blood supply to sustain oxygen and nutrients delivery. While tumor angiogenesis involves the formation of new blood vessels from pre-existing ones, vessel co-option represents a non-angiogenic vascularization strategy whereby tumor cells utilize pre-existing host vessels. Co-opted vessels have been considered refractory to anti-angiogenic therapies, and pharmacological modulation of co-opted vessels remains limited. In this study, we investigate the effects of low-dose cilengitide on tumor vascular remodeling in vessel co-option and angiogenic metastatic models. Our results reveal that cilengitide exerts distinct vascular effects depending on the mode of tumor vascularization. In vessel co-option-driven tumors, cilengitide treatment is associated with the remodeling of the co-opted vasculature into a more organized normalized vascular network, characterized by an increased number of functional blood vessels and enhanced vascular barrier integrity. In contrast, in angiogenic-driven tumors, cilengitide treatment promotes an expansion of the vascular network consistent with augmented, but structurally immature angiogenesis. Importantly, vascular remodeling in vessel co-option metastases is accompanied by enhanced blood vessel perfusion and reduced hypoxia, which correlates with enhanced responsiveness to chemotherapy. Conversely, in angiogenic metastases, the vascular network induced by low-dose cilengitide fails to support immunocompetent microenvironmental features and is associated with increased chemotherapy resistance. This study provides the first evidence that co-opted vasculature can be therapeutically targeted via integrin inhibition, suggesting vascular normalization remodeling as a potential strategy to overcome resistance in tumors undergoing vessel co-option.

CXCL12/CXCR4 signaling governs ischemic neurovascular pathophysiology and repair: a multidimensional contextual analysis - Shahram Eisa-Beygi; Hao Wu; Kui Cui; Kulandaisamy Arulsamy; Bo Zhu; Beibei Wang; Bandana Singh; Krishan Gupta; Jianing Gao; Scott Wong; Joyce Bischoff; Hanqiang Deng; et al. (Angiogenesis, 2026)

Pathogenesis and molecular mechanisms of mutant TIE2-driven venous malformation - Lindsay J. Bischoff; Elisa Boscolo (Angiogenesis, 2026)
Venous malformation (VM) is the most common subtype of vascular malformation. Due to the chronic nature of this disorder, VM patients face significant morbidity and complications throughout their lives. Current therapeutic options can be limited, but recent advances in understanding the cellular and molecular mechanisms that underly VM pathogenesis provide hope for the discovery of more effective targeted therapies. These advances arise from a greater understanding of the cellular effects of VM-causative mutations, which has been aided by the development of more advanced and physiologically relevant model systems. In this review, we begin by providing a brief overview of the clinical characteristics and genetic driver mutations of the most common subtypes of all vascular anomalies (including vascular tumors and vascular malformations), providing context for our more detailed discussion of these aspects of VM. We further summarize the current treatment options available for VM patients and the advancements that have been made in the use of targeted therapies for these patients. We further discuss recent advances in the development of model systems that can be used to study VM pathogenesis. Finally, we focus this review on the mechanisms that are downstream of mutant TIE2, discussing structural features of the receptor, TIE2 signaling pathways, and its roles in vascular physiology and VM pathology.

Antisense oligonucleotide-mediated disruption of mRNA localisation inhibits angiogenesis - Josy Augustine; Precious O. Owuamalam; Jennifer Nicell; Peter Barabas; Susanta Chatterjee; Michael O’Hare; Tim M. Curtis; Guilherme Costa (Angiogenesis, 2026)
mRNA localisation is a critical posttranscriptional mechanism that confers a spatiotemporal dimension to the control of gene expression. Among diverse outcomes, this process can result in compartmentalised protein synthesis and consequently, elicit localised cellular responses. Targeting mRNAs to their destination is often determined by localisation elements (LEs) contained in untranslated regions within targeted transcripts. Although mRNA localisation has been widely explored in the context of subcellular biology, its roles in tissue function are only just beginning to emerge. A defined set of transcripts accumulate at the leading edge of endothelial tip cells that guide emerging vessels during sprouting angiogenesis. This includes RAB13 and NET1 mRNAs, which encode proteins implicated in cytoskeletal remodelling processes underpinning cell motility. In this study, we tested the anti-angiogenic potential of antisense oligonucleotide (ASO)-based strategies designed to perturb RAB13 and NET1 localisation. Upon confirming that ASOs targeting LEs mislocalise these mRNAs without altering steady-state levels of the encoded proteins, we applied them to a series of in vitro, ex vivo and in vivo angiogenesis assays. Remarkably, the mislocalisation of RAB13 and NET1 inhibits chemotaxis and vessel sprouting in response to pro-angiogenic stimuli. Furthermore, vessel sprouting from mouse choroidal explants and retinal angiogenesis are also hindered by mRNA mislocalisation. Altogether, our strategy for disrupting spatial control of gene expression in endothelial cells opens new mechanistic avenues for the manipulation of vessel formation.

Immortalized smooth muscle cells enhance in vitro vasculogenesis - Mohammad R. Nikmaneshi; Lennard M. Weide; Noel-Adrian Hollosi; Marc A. Höll; Nemo Noeh; Franciele Filardi Cimino Silva; Dan G. Duda; Lance L. Munn (Angiogenesis, 2026)

A high-sensitivity TIE2–GRB2 BRET platform for functional and pharmacologic profiling of pathogenic variants associated with venous malformations - Hitomi Matsutani; Atsuro Oishi; Takuya Izumi-Tamura; Yumiko Hayashi; Masakazu Kurita; Tomoya Muto; Akihide Yoshimi; Hitoshi Ueno; Tomohiro Shiraishi; Kiyonori Harii; Akihiko Takushima; Hiroyasu Kidoya; et al. (Angiogenesis, 2026)

Smad3 deficiency attenuates disease severity in a zebrafish model for Smad6-related aortic disease - Michiel Vanhooydonck; Maxim Verlee; Marta Santana Silva; Lore Pottie; Annekatrien Boel; Matthias Van Impe; Hanna De Saffel; Lisa Caboor; Anne Bonnin; Patrick Segers; Adelbert De Clercq; Yannick Gansemans; et al. (Angiogenesis, 2026)

Lysosomal channel TPC2 modulates microglia-endothelial signaling in choroidal angiogenesis - Yi Lu; Alice Reschigna; Franz Kynast; Zhuo Yang; Maximillian Gerhardt; Pavel Kielkowski; Siegfried Priglinger; Martin Biel; Stylianos Michalakis (Angiogenesis, 2026)
Pathological choroidal neovascularization underlies vision loss in neovascular age-related macular degeneration (nAMD), yet the molecular regulators coordinating vascular and immune components remain incompletely defined. Here, we investigated the role of the endolysosomal cation channel, two-pore channel 2 (TPC2) in choroidal angiogenesis. Loss of TPC2 in mice markedly reduced ex vivo choroidal sprouting, while pharmacological activation enhanced vascular growth. Mechanistically, Tpc2 -deficiency led to downregulation of multiple microglia-derived pro-angiogenic factors and impaired the ability of the microglial secretome to stimulate neovascularization. In choroidal vascular cells, TPC2 loss attenuated NF-κB/MAPK signaling pathways. Tpc2 -deficiency is also associated with lysosomal secretion of cathepsins, especially CTSD, resulting in decreased extracellular proteolytic activity and impaired paracrine regulation of angiogenesis. Extending these findings to human cells, TPC2 knockout in iPSC-derived endothelial cells impaired migration, tube formation, and CTSD activity in the secretome, mirroring the murine phenotype. Together, these results establish TPC2 as one of the regulators of lysosome-mediated choroidal angiogenesis, highlighting its potential as a therapeutic target in nAMD.

Long-term angiogenic and thromboinflammatory signatures in post-COVID-19 syndrome - Arlette Araceli Mora Zetina; Erika Fabiola Ortega Sanchez; Brenda Saraí Zuñiga Ascencio; Armando Roberto Castorena Maldonado; Víctor Hugo Ahumada Topete; Luz María Torres Espíndola; Arnoldo Aquino Gálvez; Rosario Fernández Plata; Anjarath Lorena Higuera Iglesias; David Martínez Briseño; Aranza Bernal Silva; Misael Osmar García Martín; et al. (Angiogenesis, 2026)

3D co-culture model of tumor spheroid and endothelial cells unveils ccRCC aberrant vasculature and distinct sensitivity to targeted treatments - Noémie Brassard-Jollive; Yoann Atlas; Camille L. M. Compère; Corinne Ardidie-Robouant; Philippe Mailly; Morad El Bouchtaoui; Virginie Lelarge; Guillaume Blot; Nathalie Josseaume; Stéphanie De Oliveira; Christophe Helary; Christophe Leboeuf; et al. (Angiogenesis, 2026)

Functional definition of endothelial progenitors by PROCR and PDGFRA co-expression - Cassandra Styke; Simranpreet Kaur; Seen-Ling Sim; Jilai Zhao; Chenhao Zhou; Ho Yi Wong; Jatin Patel; Edwige Roy; Mervyn C. Yoder; Richard P. Harvey; Abbas Shafiee; Kiarash Khosrotehrani (Angiogenesis, 2026)
The functional and molecular definition of progenitors giving rise to blood vessel endothelium in vivo remains disputed. Upon investigating the overlap of seemingly divergent reports currently defining putative endothelial progenitor cells (EPCs) using single-cell RNA-sequencing and flow cytometry, Protein C Receptor (PROCR) and Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) largely overlapped with previously characterized murine aorta’s CD34 + CD31 low endovascular progenitors (EVPs). Functional assays and lineage tracing in homeostatic aorta and excisional wounds demonstrated increased clonogenic capacity, engraftment potential, and ability to form differentiated endothelial (D) cells of PROCR + PDGFRA + EPCs, termed as refined endothelial progenitor cell (rEPC), as compared to PROCR neg PDGFRA neg EVPs. Similar PROCR and PDGFRA expression in normal human aorta, and increased clonogenic capacity of CD34 + CD31 low PROCR + endothelial cells from freshly isolated human term placenta were observed as compared to controls. Functional validation of human rEPCs is supported by PROCR enrichment, while PDGFRA co‑expression in human endothelial progenitor–like cells is supported at the transcriptomic level only. Thus, overlapping PROCR and PDGFRA expression in EVPs narrows the population with true functional progenitor capacity.

Critical role of endothelial regulator of G protein signaling 5 in postnatal angiogenesis - Nikola Sladojevic; Haw-Chih Tai; Dhiraj Patel; Maryam Emami; James K. Liao (Angiogenesis, 2026)

Semi-automated quantification of total and avascular retinal area in the rat model of oxygen-induced retinopathy - Husaam Qureishy; Amelia Morikuni; Michael D. Evans; Rehan Krishnan; Ellen C. Ingolfsland (Angiogenesis, 2026)

Endothelial VEGFR2 insufficiency promotes the transition of lymphatic to hematopoietic transcriptional programs - Taotao Li; Xudong Cao; Fei Zhou; Xiujuan Li; Wenjuan Ma; Xiuyan Zhang; Haoyu Zhong; Beibei Xu; Man Chu; Xiwen Jia; Kai Ding; Xin Shen; et al. (Angiogenesis, 2026)

Endothelial Notch1 drives multicellular remodelling during hyaloid vessel regression - Shaymaa Khazaal; Abdoul-Razak Sango; Kawtar Zouine; Alexa Silva Sosa; Ariane Vanessa Megne; Rony Chidiac; Kiran Bora; Gaelle Mawambo; Jing Chen; Malika Oubaha (Angiogenesis, 2026)

Endothelial protein C receptor and the endothelial progenitor paradigm: towards a functional definition at last - David M. Smadja (Angiogenesis, 2026)

Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer - Jesus Gomez-Escudero; Eleni Maniati; Julie Holdsworth; Gordon Beattie; Maruan Hijazi; Matt Guelbert; Samar Elorbany; Pedro Cutillas; Jun Wang; Kairbaan Hodivala-Dilke; Gabriela D’Amico (Angiogenesis, 2026)
Despite its established role in breast cancer treatment, Doxorubicin treatment remains subject to adaptive resistance mechanisms that extend beyond cancer cell intrinsic alterations ultimately reducing therapy efficacy. Our study in a MMTV-PyMT-driven mouse breast cancer model reveals that prolonged Doxorubicin (Dox) exposure triggers significant reprogramming of the tumour vasculature, substantially altering the angiocrine landscape and shaping treatment outcomes. Notably, tumours that initially respond, but later revert, display an endothelial cell subclustering with activation of proliferative and NF-κB-dependent cytokine pathways. We further identify a novel endothelial subpopulation characterised by higher expression of drug clearance and oxidative metabolism markers, suggesting an active role in mitigating Dox efficacy and angiogenesis promotion. These findings substantiate endothelial plasticity as a critical mediator of therapeutic failure. By uncovering these vascular adaptations, our work provides a new perspective on the underlying mechanisms of Dox resistance and the prolonged efficacy of chemotherapy in breast cancer.

A possible microvascular vulnerability in carotid artery dissection: insights from nailfold capillaroscopy - Angelo Nigro; Sandro Sanguigni; Giuseppe Nicoletti (Angiogenesis, 2026)

MCC links Wnt/PCP signaling to endothelial polarity and vascular remodeling - Valentin Delobel; Béatrice Jaspard; Malvina Salami; Marion Camoin; Claire Peghaire; Juliette Vaurs; Romain Boulestreau; Alexandre Dubrac; Thierry Couffinhal; Cécile Duplàa (Angiogenesis, 2026)

miR-150 controls developmental angiogenesis via ribosome biogenesis-dependent regulation of Notch signaling - Haotian Kong; Kang Ai; Jinghe Zhang; Ziting Liu; Yue Wu; Li Zhang; Huixin Zhang; Xiuli Chen; Linglu Li; Yuanyuan Fu; Xiaojing Wang; Lei Li (Angiogenesis, 2026)

From endothelial epigenetic switching to a vascular-readiness compass for cancer immunotherapy - M. Vijayasimha; M. Srikanth; Keerthi Rao (Angiogenesis, 2026)

Endothelial AGO1 deficiency reduces breast cancer burden in mice - Xuejing Liu; Alonso Tapia; Dongqiang Yuan; Xiaofang Tang; Yingjun Luo; Naseeb Kaur Malhi; Muxi Chen; Kwan Ho Law; Mohamad Haidar; Skylar Giacobetti; Jiawei Sun; Anthony Park; et al. (Angiogenesis, 2026)
Endothelial cells (ECs) are crucial in cancer development and progression, partly by regulating tumor angiogenesis and immune modulation. As a key component of the RNA-induced silencing complex, Argonaute 1 (AGO1) regulates tumor biology, yet the specific function of AGO1 within ECs in the tumor microenvironment remains undefined. Here, we investigated the effects of endothelial-specific AGO1 knockout (EC-AGO1-KO) on tumor vascularization and immune regulation in a mouse syngeneic breast cancer model induced by E0771 cells. EC-AGO1-KO mice exhibited significantly reduced tumor burden compared to their wild-type (WT) littermates, accompanied by reduced vascularization and enhanced immune cell infiltration. Histological and single-cell RNA sequencing analyses revealed increased infiltration of CD8⁺ T cells and macrophages in EC-AGO1-KO tumors, indicative of an immunostimulatory microenvironment. In vitro, AGO1 knockdown in mouse ECs co-cultured with E0771 tumor cells led to higher levels of Cxcl10 and Vcam1 expression, suggesting a pro-inflammatory and leukocyte-recruiting effect. Together, these findings identify endothelial AGO1 as a key regulator of tumor vasculature and immune homeostasis in breast cancer, suggesting that targeting endothelial AGO1 may represent a novel therapeutic strategy to modulate tumor vasculature while enhancing anti-tumor immunity.

Soluble CD146 reflects altered endothelial and metabolic homeostasis in peripheral artery disease - Haizam Oubari; Julien Labreuche; Charlotte Reytier; Françoise Dignat-George; Jean-Paul Duong-Van-Huyen; Joseph Emmerich; Pascale Gaussem; Patrick Bruneval; Marcel Blot-Chabaud; Alexandre G. Lellouch; Nathalie Bardin; David M. Smadja (Angiogenesis, 2026)
Background Peripheral Arterial Disease (PAD) is a prevalent but underdiagnosed pathology. Soluble CD146 (sCD146) was described as a marker of endothelial dysfunction and vascular congestion. Objective We hypothesize that sCD146 may represent a novel biomarker of PAD. Our objective was to evaluate the association between plasma sCD146 levels and the occurrence and severity of PAD. Methods In this case–control study, 184 Caucasian men with symptomatic PAD were compared to 163 age-matched healthy control patients. PAD diagnosis was confirmed using ankle-brachial index (ABI) and imaging. Plasma sCD146 was quantified using ELISA. Associations with clinical and biochemical parameters were analyzed through multivariable logistic regression models. Results sCD146 level was significantly reduced in PAD patients (mean [95% CI]: 288 ng/mL [269–306]) versus control patients (480 ng/mL [460–500], p p p = 0.005), but negatively correlated in PAD patients (β = − 0.156, p = 0.041), with significant interaction ( p = 0.002). Age-adjusted OR for PAD was highest in individuals with high HDL-C tertiles (OR = 1.41, 95% CI 1.22–1.63). Conclusion A lower sCD146 concentration is independently associated with PAD. Additionally, an inverse relationship was observed between HDL-C and these patients. These findings suggest that sCD146 may reflect impaired endothelial homeostasis and metabolic dysregulation in PAD, indicating that it could serve as a diagnostic biomarker for the pathology. Clinical trials registration : NCT00377897.

An Rnf213-deficient hypoperfusion model reveals Moyamoya-relevant neurovascular remodeling - Yuanyuan Dai; Xiaoxin Wu; Shuai Li; Xingyang Niu; Jiaoxing Li; Jianhao Lin; Wenli Sheng (Angiogenesis, 2026)

Characterizing pancreatic cancer-associated fibroblast heterogeneity in vascular microphysiological systems - Charles W. Blackledge; Sarah Gullion; Ian McCabe; Ngan N. K. Van; Arthi Hariharan; Changfei Luan; Xianlu Laura Peng; William J. Polacheck; Jen Jen Yeh; Sarah E. Shelton (Angiogenesis, 2026)
Pancreatic Ductal Adenocarcinoma (PDAC), one of the deadliest cancer types, is dominated by a tumor microenvironment (TME) that is desmoplastic, immunosuppressive, and generally unresponsive to conventional cancer treatments. Cancer-Associated Fibroblasts (CAFs) are thought to drive many of the features of PDAC that contribute to treatment resistance, yet CAFs exhibit wide phenotypic heterogeneity with unclear biological and clinical implications. Recent work has identified CAF subtypes – tumor-restraining CAFs (RestCAFs) or tumor-promoting CAFs (ProCAFs) – that correlate with overall survival. Therefore, this study aims to identify CAF subtype-dependent functional effects in the TME using 3D microphysiological systems, focusing primarily on their interactions with vasculature. Microfluidic devices including a RestCAF line demonstrated increased levels of vasculogenesis and extracellular matrix remodeling, while devices containing a ProCAF line exhibited increased angiogenic sprouting and differential immune cell recruitment, such as monocyte migration into the TME. This work provides novel insights into the heterogeneous functions of CAFs in the TME and lays important groundwork for the development of CAF-targeted therapies in PDAC.

Prevascularized grafts with spatially organized MSC spheroids to accelerate therapeutic angiogenesis in ischemic disease - Jeonghyun Son; Aruzhan Naren; Hanan Jamal Mohamed; Minjun Ahn; Won Ha; Min Kyeong Kim; Seunggyu Jeon; Byoung Soo Kim; Yoon-Kyoung Cho; Shoji Takeuchi; Hyun-Wook Kang (Angiogenesis, 2026)

Congenital portosystemic shunt with extensive collateralization in an adult with recurrent episodes of hyperammonemic encephalopathy - David Melville; Mayowa A. Osundiji (Angiogenesis, 2026)

Transcriptomic characters of cochlear vascular cells with pericyte-driven angiogenetic activity - Pingting Wang; Yunpei Zhang; Zhiqiang Hou; Jinhui Zhang; Kushal Sharma; Xiaorui Shi (Angiogenesis, 2026)

HDAC inhibition reprograms stem cell fate to suppress infantile hemangioma vasculogenesis - Qiming Chen; Hao Rong; Chao Liu; Jiang Li; Jiawei Zheng; Qian Bian (Angiogenesis, 2026)

Endothelialization of bioprosthetic valves: unanswered questions and a roadmap for translational research - Bo jiang; Hongjun Liu (Angiogenesis, 2026)

Portal vein embolization versus radiation lobectomy as pre-treatment for major liver resection for colorectal liver metastases: functional assessment of the future liver remnant - Khalil Ramdhani; Rosalie C. M. van Rees; Daan Andel; Jeanine M. L. Roodhart; Arthur J. A. T. Braat; Rutger C. G. Bruijnen; Inne H. M. Borel Rinkes; Onno Kranenburg; Marnix G. E. H. Lam; Maarten L. J. Smits; Jeroen Hagendoorn (Angiogenesis, 2026)
Introduction Insufficiency of the future liver remnant (FLR) precludes surgery for liver tumors as it is associated with post-hepatectomy liver failure (PHLF). A common strategy to induce pre-operative FLR hypertrophy is portal vein embolization of the tumor bearing liver lobe. More recently, transarterial radio-embolization (radiation lobectomy, RL) has been employed. Direct functional assessment using 99mTc-mebrofenin-hepatobiliary-scintigraphy (HBS) predicts FLR sufficiency more accurately than conventional volume assessment. However, studies describing dynamic functional assessment of the FLR after RL as induction for surgery are currently lacking. This study aims to compare FLR functional changes after PVE and RL. Methods This non-interventional retrospective single-center cohort study was performed between 2016 and 2024. Patients with colorectal liver metastases (CRLM) who underwent PVE or RL because of an insufficient FLR (HBS 2 ) were included. Induction of sufficient FLR function was the primary outcome. Results Ten PVE- and ten RL-treated patients were included. The median duration to achieve sufficient FLR function was longer for RL- than PVE-treated patients (75 days (64–85) vs 31 days (28–54.5), p = 0.002). RL showed a non-significant higher median functional increase (58.6% vs 51.1%, p = 0.940) and a significantly higher voluminal increase (65.7% vs 36.8%, p = 0.049) compared to PVE. PHLF and resection margins were comparable among groups. There was no 90 day mortality. Conclusion RL represents a feasible alternative to PVE with comparable functional outcomes, particularly in patients with lower baseline FLR function or need for simultaneous tumor control. This warrants prospective studies with optimized RL protocols to better define the functional outcomes and clinical applications of RL versus PVE.

An epigenetic switch in vascular phenotype augments anti-tumor immunity - Dae Joong Kim; Mitchell McGinty; Swetha Anandh; Caroline Riedstra; Yuvraj Sethi; Melanie R. Rutkowski; Andrew C. Dudley (Angiogenesis, 2026)
The abnormal tumor vasculature can present a barrier to the infiltration of anti-tumor immune cells, which impairs immune surveillance and response to immunotherapy. Here, we show that genetically deleting the epigenetic factor DNA methyltransferase 1 ( Dnmt1 ) in endothelial cells (ECs) reduces angiogenesis while imparting profound changes to the tumor immune microenvironment (TIME), including increased proportions of CD4 + memory T cells and NK cells. Depleting CD4 + T cells, or blocking lymphocyte egress from the lymph nodes, rescues tumor growth in mice with conditional deletion of Dnmt1 in ECs ( Dnmt1 iECKO ) and dramatically shortens overall survival, whereas NK cells are dispensable. Tumors implanted in Dnmt1 iECKO mice show reduced vascular branching, elevated expression of VCAM1, increased vessel-associated T cells, and a shift in vascular specification, including increased proportions of immune-permissive post-capillary venules (PCVs) and interferon-stimulated ECs (IFN-ECs). Deleting Dnmt1 in EC cultures strikingly potentiates responses to combinations of IFNγ and TNFα and, notably, up-regulates important T-cell co-stimulatory molecules for memory CD4 + T cells, including Icosl , Cd40 , and Tnfsf4 . Finally, immune checkpoint blockade (ICB) administered to Dnmt1 iECKO mice with experimental melanoma lung metastasis reduces tumor burden, with some mice showing tumor eradication. Our findings identify endothelial Dnmt1 as a key regulator of vascular-mediated anti-tumor immunity, providing a rationale for integrating epigenetic modulation of the vasculature with cancer immunotherapy regimens.

CreER activation transiently disrupts angiogenesis by reducing proliferation and promoting apoptosis in vascular endothelial cells - Elena Ioannou; Mengmeng Dong; Victoria S. Rashbrook; Christiana Ruhrberg; Martina Rudnicki (Angiogenesis, 2026)
Tamoxifen-inducible gene targeting in mice with estrogen receptor-dependent Cre (CreER) recombinase has enormously advanced vascular biology research. However, CreER activation under the control of vascular endothelial promoters causes off-target effects that impair the vascularization of the retina, a widely used model to study the molecular and cellular mechanisms of angiogenesis. Although ubiquitously expressed CreER is also used to study retinal angiogenesis, it remains unknown whether it causes similar or more severe off-target effects compared to endothelial-selective CreER activation. Moreover, the molecular and cellular processes disrupted by CreER activation in endothelial cells remain to be identified. Here, we demonstrate that ubiquitous CreER activation in postnatal mice decreases body growth and impairs retinal angiogenesis. We further show that CreER activation slows endothelial cell proliferation and promotes apoptosis concomitant with p21/CDKN1A upregulation in the angiogenic retina, although retinal vasculature progressively normalizes. By contrast, CreER activation in quiescent adult retinal vasculature did not induce endothelial cell apoptosis or p21 activation. Altogether, our findings indicate that ubiquitous promoters should be avoided to drive CreER expression when studying gene function during retinal angiogenesis, and that CreER activation controls, although essential to account for endothelial apoptosis and proliferation defects in short-term studies, may be less critical for adult vascular studies.

Neuropilin 1 (NRP1) conveys SEMA3A signals to restrict physiological angiogenesis - Marco Spreafico; Elena Guzzolino; Francesca Fanuele; Gaia Gestri; Carlotta Tacconi; Sara Palermo; Matilde Tricco; Valeria Catroppa; Ayazhan Aiypova; Laura Denti; Caroline Pellet-Many; Christiana Ruhrberg; et al. (Angiogenesis, 2026)
The class 3 semaphorin SEMA3A is a secreted glycoprotein that serves as an evolutionary conserved axon repellent with proposed vascular functions. In mice, SEMA3A is dispensable for developmental brain, limb or trunk blood vessel patterning, but restricts vessel branching in the zebrafish embryo trunk. Whereas neuropilin 1 (NRP1) is thought to be the SEMA3A receptor in the mouse, prior reports identified Plexin D1 as the Sema3a receptor in zebrafish trunk vessel patterning, with previous knockdown and knockout studies yielding contradictory results on Nrp1 requirement for vessel patterning in zebrafish. To resolve these discrepancies, we have refined the prior knockdown strategy to limit off target effects and generated mutant zebrafish embryos lacking both Nrp1a and Nrp1b paralogues to show that Nrp1 restricts trunk vessel patterning in a Sema3a-dependent manner. In agreement, we found that NRP1 is required in human endothelial cells for SEMA3A-induced repulsion. Moreover, we show that SEMA3A action via NRP1 does not involve the splicing regulation of FLT1 , previously proposed to act downstream of Plexin D1. Instead, sustained NRP1 activation independent of SEMA3A increases the expression of the anti-angiogenic soluble FLT1 (sFLT1), establishing a feedback mechanism to limit endothelial proliferation. Together, these findings demonstrate a dual role for NRP1 in shaping physiological vascular morphogenesis. Thus, NRP1 mediates repulsive SEMA3A cues in endothelial cells, in analogy to its role in axon guidance, and further restricts angiogenesis by promoting the release of sFLT1 in a SEMA3A-independent manner.

A human endothelial and adipose stem cell-based co-culture model for venous malformations - Mohammadhassan Ansarizadeh; Bojana Lazovic; Zahra Sarmadian; Abhishek Singh; Ryan Hicks; Lauri Eklund (Angiogenesis, 2026)
Venous malformations (VMs) are developmental defects in vascular morphogenesis characterized by enlarged vein-like channels and defective perivascular cell coverage. The majority of VMs are caused by somatic mutations in endothelial cell (EC) receptor tyrosine kinase TIE2, but current medicinal options are limited. The common bottleneck when testing new therapeutic strategies and identifying efficient drug candidates is the absence of a reliable and robust model for replicating the characteristics of VMs. We report here on an advanced in vitro model for recapitulating cellular and molecular pathologies of the VM-causative TIE2 L914F mutation by co-culturing human adipose tissue-derived stem cells (hASCs) with either human umbilical vein ECs (HUVECs) retrovirally transduced to express TIE2 L914F or with induced pluripotent stem cell-derived ECs (iECs) with locus-targeted TIE2 L914F . For comparison, cellular and molecular crosstalk between vascular cell types was investigated in HUVEC and primary vascular smooth muscle cell (vSMC) co-cultures. Advanced microscopy and transcriptomic analysis were used to investigate the cellular and molecular phenotypes in vascular cell types. Comparison of TIE2 WT , gain- ( TIE2 L914F ) and loss-of-function mutations ( TIE2 KO ) revealed the importance of TIE2 signaling for vascular network formation in hASC/EC co-cultures. The model recapitulated the cellular hallmarks of the VMs and revealed gene signatures and signaling pathways relevant to VM pathologies. The data also demonstrated the utility of the hASC/EC model as a screening platform for VM pharmacotherapies. Overall, this work establishes a versatile platform for studying disease mechanisms affecting the vasculature and provides new insights into VM pathobiology and screening potential for therapeutic applications targeting VMs.

Platelet-derived growth factor receptor β F7 mutations result in and exacerbate the severity of vascular dysplasia in the brain arteriovenous malformation through enhancing angiogenesis - Alka Yadav; Leandro Barbosa Do Prado; Mustafa Mohamed; Calvin Wang; Joshua Shi; Zahra Shabani; Rich Liang; Kelly Press; Courtney Tom; Ethan A. Winkler; Hua Su (Angiogenesis, 2026)
Brain arteriovenous malformations (bAVMs) are tangles of abnormal vessels that shunt blood directly from arteries to veins. The reduction of pericytes is linked to hemorrhage in bAVMs. The Pdgfb/Pdgfrβ signaling pathway is crucial for regulating pericyte recruitment during angiogenesis. Here, we show that mice with Pdgfrβ F7 mutations developed cerebrovascular dysplasia in the brain’s angiogenic region, associated with increased pro-angiogenic and inflammatory signaling. Interestingly, the expression of activin receptor-like kinase 1 (Alk1) is decreased in the brain’s angiogenic region of Pdgfrβ F7 heterozygous mice. Overexpression of ALK1 in brain endothelial cells (ECs) reduces angiogenic signaling and the severity of vascular dysplasia in Pdgfrβ F7 heterozygous mice. Pdgfrβ F7 mutations also increased dysplastic vessels and reduced pericyte coverage in the bAVM in endoglin-deficient mice. Endoglin is an AVM causative gene. Our data indicate that Pdgfrβ F7 mutations result in cerebrovascular dysplasia and worsen the bAVM phenotype in endoglin mutant mice by enhancing angiogenesis and inflammation. Overexpression of ALK1 in brain ECs reduces the severity of cerebrovascular dysplasia in Pdgfrβ F7 heterozygous mice through downregulating angiogenic signaling.

Evolving biopsy strategies for molecular profiling of brain arteriovenous malformations - Zhenghong Peng; Li Zhang; Jiasen Ye; Zuoyue Duan; Tianqi Tu (Angiogenesis, 2026)

Reconsidering the metabolic specificity of ACLY-dependent angiogenesis - Yan Zhang (Angiogenesis, 2026)

PINCH proteins as dual-function nodes in vascular mural cell homeostasis: from cytoplasmic scaffolds to nuclear gatekeepers - Bo Jiang; Hongjun Liu (Angiogenesis, 2026)

Correction: Endothelial LRRC8A mitigates pressure overload-induced cardiac hypertrophy by promoting coronary angiogenesis - Lingjun Jie; Baolong Feng; Yufan Zhou; Chan Du; Wenlin Zhou; Ruonan Zhang; Wei Shen; Jiajin Chen; Penglong Wu; Xu Kong; Yuliang Zhan; Meimei Shi; et al. (Angiogenesis, 2026)

The vascular contribution to immunotherapy success - Arjan W. Griffioen; Judy R. van Beijnum; Sacha Jacobs; Mattie Cassee; Myra Castel; Patrycja Nowak-Sliwinska (Angiogenesis, 2026)

PINCH proteins orchestrate vascular mural cell homeostasis through integrated signaling and transcriptional networks - Chunxiao Wang; Yao Jin; Yuanfeng Xin; Qianke Xing; Hongming Zhu; Qicheng Zou; Jie Yan; Lina Luo; Xingqun Liang; Yunfu Sun; Zhongmin Liu (Angiogenesis, 2026)

Progressive endothelial coverage enhances hemocompatibility and prevents calcification in bioprosthetic valve tissue - Bastien Poitier; Ulysse Richez; Joseph Roux-de-Bezieux; Peter Ivak; Jeanne Rancic; Hugo Charrier; Christian Latremouille; Christophe Peronino; Jean Christian Roussel; Elisa Rossi; Salma El-Batti; Michel Kindo; et al. (Angiogenesis, 2026)

ATP-citrate lyase is a critical regulator of physiological and pathological angiogenesis - Chong Xu; Ying Lin; Zeyu Wang; Cailin Feng; Lingfeng Luo; Shuai Guo; Han Zhang; Lu Liu; Azhen Fan; Penglong Qi; Dongyang Jiang; Yiming Xu; et al. (Angiogenesis, 2026)

Exploiting porphyrin metabolism to inhibit angiogenesis - Francesco De Giorgio; Giuseppe Mannino; Veronica Bonalume; Alessia Bibi; Cristina Martorana; Sabrina Digiovanni; Chiara Riganti; Tullio Genova; Luca Munaron; Christiana Ruhrberg; Alessandro Fantin; Sara Petrillo; et al. (Angiogenesis, 2026)
Heme is an essential iron-containing porphyrin that plays a critical role in endothelial cell (EC) function, regulating processes such as cell signalling and energetic metabolism. Nevertheless, the role of de novo heme synthesis and porphyrin metabolism during angiogenesis remains poorly understood. In this study, a pharmacological approach using 5-aminolevulinic acid (ALA) was employed to dysregulate heme/porphyrins homeostasis in EC. ALA treatment resulted in intracellular porphyrins accumulation and extensive release into the extracellular environment. ALA-treated EC exhibited diminished proliferation and migration, as well as reduced ability to form tubule-like structures, which led to impaired ex vivo angiogenic sprouting and in vivo angiogenesis in the developing retina. Moreover, ALA inhibited pathological neovascularization in the oxygen-induced retinopathy mouse model that recapitulates the vascular alterations occurring in human patients affected by retinopathy of prematurity and diabetic retinopathy. Importantly, extracellular porphyrins contributed to the observed anti-angiogenic effects. These findings underscore the biological impact of endogenous porphyrins on EC function and angiogenesis, providing insights into potential therapeutic applications for human diseases characterized by aberrant vascularization, including neovascular eye diseases.

Making sex-specific endothelial OCT4 biology implementation-ready: separating chromosomal and hormonal effects and standardizing translational endpoints - M. Vijayasimha; M. Srikanth; Rajeev Kumar Jha (Angiogenesis, 2026)

Vascular normalization by erianin unleashes CAR-T immunotherapy in glioblastoma - Shiling Zhou; Shuyi Qian; Bowen Sun; Peng Shi; Shanni Guo; Changrui Yang; Jiwei Zhang; Yanqing Gong; Fan Yang (Angiogenesis, 2026)

Advanced technologies of artery-on-a-chip: a review of construction strategies and disease models - Shi-Qi Chang; Li Qiao; Oluwatosin David Abodunrin; Lin Zou; Ning-Ping Huang (Angiogenesis, 2026)

Calcineurin-NFAT-DSCR1.4 signaling as druggable axis in Gαq-R183Q–driven capillary malformations - Tong Xu; Vera Janssen; Nathalie R. Reinhard; Paula Sobrevals-Alcaraz; Robert M. van Es; Annett de Haan; Julian de Swart; Martijn Wehrens; Hannah de Kraker; Albert Wolkerstorfer; Chantal M. A. M. van der Horst; Harmjan R. Vos; et al. (Angiogenesis, 2026)
Capillary malformations (CMs) are congenital vascular lesions caused by somatic mutations in the GNAQ gene, most frequently resulting in a p.R183Q substitution in the Gαq protein in endothelial cells. However, the downstream signaling pathways by which Gαq-R183Q impairs vascular function remain poorly defined. To address this, we generated human dermal endothelial cells lacking endogenous Gαq and expressing the Gαq-R183Q mutant. Next, using SILAC-based quantitative proteomics, we mapped the Gαq-R183Q-induced endothelial phosphoproteome. These analyses identified aberrant activation of the Calcineurin–NFAT–DSCR1.4 signaling cascade as a key pathogenic feature. NFAT dysregulation and DSCR1 expression in endothelial cells were confirmed in patient-derived biopsies. Pharmacological inhibition of Calcineurin with tacrolimus partially normalized NFAT signaling in Gαq-R183Q endothelial cells. Strikingly, genetic depletion of DSCR1 in Gαq-R183Q cells fully restored Calcineurin/NFAT signaling and enabled proper endothelial migration and angiogenic sprouting, highlighting DSCR1 as a critical effector of Gαq-R183Q signaling in CMs. These findings reveal a druggable signaling circuit downstream of Gαq-R183Q that may serve as a foundation for future therapies targeting GNAQ -driven vascular malformations, including Sturge-Weber syndrome.

Endothelial USP8 is essential for angiogenesis - Alba Pau-Navalón; Tamara González-Costa; María Lancho Lavilla; Andrés A. Urrutia; José Luis de la Pompa; Henar Cuervo; Joaquim Grego-Bessa (Angiogenesis, 2026)

Deletion of the angiopoietin receptor Tie2 enhances proliferation and sprouting of cardiac endothelial cells - Andrey Anisimov; Madeleine H. Lackman; Hellmut G. Augustin; Eero Mervaala; Kari Alitalo; Sinem Karaman (Angiogenesis, 2026)
Background Endothelial cells (ECs) of the heart proliferate and form new vessels in response to vascular endothelial growth factor (VEGF), but VEGF has not benefited the therapy of cardiac ischemia because of its side effects. Here, we explored if deletion of the vascular steady-state homeostasis maintaining Tie1 and Tie2 receptor tyrosine kinases affects the proliferation and sprouting of cardiac ECs. Methods We analyzed EC proliferation and histological and immunohistochemical stainings by confocal microscopy, plus scRNA and qPCR analyses of gene expression in the heart, kidneys, and lungs of Tie1 fl/fl , Tie2 fl/fl , and Tie1 fl/fl ; Tie2 fl/fl mice, in which vascular endothelial cadherin-driven CreER T2 recombinase was used to delete Tie1 , Tie2 or both receptors. These analyses were also performed in mice subjected to transverse aortic constriction (TAC). Boyden chamber assays were performed to assess the migration of cultured ECs in cultures with or without TIE receptor silencing. Results Genetic deletion of Tie1 , Tie2 , or Tie1/Tie2 in mice increased significantly the proliferation of cardiac but not renal or pulmonary ECs, as measured by EdU incorporation into DNA and quantification of the cell cycle marker cyclin D1. Tie1/Tie2 or Tie2 deletion, but not Tie1 deletion alone, induced EC sprouting in coronary vasculature and expression of endothelial tip cell markers, including expression of the FOXO1-regulated Angpt2 and Esm1 genes in cardiac versus kidney or lung ECs. Consistent with these findings, silencing of TIE2 , but not TIE1 , in cultured ECs resulted in increased migration of ECs. Similar results were obtained in mice subjected to TAC. Conclusion Deletion of Tie2 alone or together with Tie1 increases the proliferation and sprouting of cardiac, but not renal or pulmonary ECs, without to neovessel formation in the heart.

Systemic microangiopathy unmasked by nailfold capillaroscopy in vertebral hemangiomas - Angelo Nigro (Angiogenesis, 2026)

Secreted frizzled-related proteins in angiogenesis: molecular mechanisms and clinical implications - Wei Wu; Yukun Zhang; Weihua Song; David Virshup; Xiaomeng Wang (Angiogenesis, 2025)

IL-6 trans-signaling: an overlooked driver of retinal neovascularization? - Malte Jung; Jan N. Ness; Melanie E. Schwämmle; Julian Rapp; Stefaniya Boneva; Olaf Groß; Julia Mitschke; Günther Schlunck; Hansjürgen Agostini; Luciana Hannibal; Felicitas Bucher (Angiogenesis, 2025)
Background Vascular endothelial growth factor (VEGF) is regarded as the essential promoter of vitreoretinal vascular diseases that threaten eyesight, such as proliferative diabetic retinopathy (PDR). Therefore, VEGF is the primary therapeutic target in these diseases, but not all patients respond adequately to VEGF inhibition. This raises the question if other factors contribute to disease modulation. PDR evolves in an interplay of pathological processes including inflammation, barrier integrity loss, aberrant angiogenesis, and metabolic dysregulation. Interleukin-6 (IL-6), recognized for its pro-inflammatory properties, was the focus of this study. Aim Investigate IL-6 mediated angiogenic potential and disease-relevant mechanisms in the context of VEGF driven vitreoretinal disorder. Methods Levels of IL-6 and soluble IL-6 receptor (sIL-6R) were quantified in patient samples using ELISA. In vitro, the functional effect and downstream signaling patterns of IL-6, sIL-6R and VEGF on vascular endothelial cells were analyzed with western blot, spheroid sprouting-, migration-, seahorse assays and LC–MS/MS. Results Vitreous samples from PDR patients showed elevated levels of IL-6 and its corresponding soluble IL-6 receptor (sIL-6R) compared to clinical control groups. In vitro, IL-6 trans-signaling (IL-6 + sIL-6R) leads to a pro angiogenic phenotype in human vascular endothelial cells demonstrated in migration and spheroid sprouting assays, mirroring the effects of VEGF. Interestingly, IL-6 trans- and VEGF-signaling differ in their effects on barrier integrity and metabolic profile. IL-6 trans-signaling disrupts endothelial barrier function and shows an increased mitochondrial oxygen consumption rate in the Seahorse assay, as well as lower produced lactate levels compared to VEGF. Tocilizumab, an IL-6R antibody, showed additive treatment effects to anti-VEGF therapeutics regarding angiogenesis and VEGF induced metabolic drive in vitro. Conclusion IL-6 trans-signaling functions as an independent promoter of vitreoretinal vascular disease and therapeutic targeting of its pathway could beneficially complement current anti-VEGF treatment protocols.

Sex-specific angiogenic responses in endothelial cells—role of the pluripotency factor OCT4 - Junchul Shin; Junyoung Hong; Iuliia Molokotina; Irene Krukovets; Ellin Kim; Svyatoslav Tkachenko; Eugene Podrez; Tatiana V. Byzova; Olga A. Cherepanova (Angiogenesis, 2025)

Hydroxychloroquine does not affect endotheliopathy or coagulopathy biomarkers in COVID-19: longitudinal results from the DisCoVeRy randomized trial - Clément R. Massonnaud; Maya Hites; Nathan Peiffer-Smadja; Jeanne Rancic; Yazdan Yazdanpanah; Sophie Luneau; Annabelle Dupont; Christelle Delmas; Jean-Luc Diehl; Aurélien Philippe; Sophie Susen; France Mentré; et al. (Angiogenesis, 2025)

Endothelial LRRC8A mitigates pressure overload-induced cardiac hypertrophy by promoting coronary angiogenesis - Lingjun Jie; Baolong Feng; Yufan Zhou; Chan Du; Wenlin Zhou; Ruonan Zhang; Wei Shen; Jiajin Chen; Penglong Wu; Xu Kong; Yuliang Zhan; Meimei Shi; et al. (Angiogenesis, 2025)

Integrative single cell RNA and spatial profiling identify mechanisms of neonatal brain hemorrhage pathophysiology and repair - Santiago A. Forero; Zhihua Chen; Ali Pirani; Arpan De; Zachary Wise; Xiaofeng Zheng; John E. Morales; Joseph H. McCarty (Angiogenesis, 2025)

Executive summary of the 15th HHT international scientific conference - Freya Droege; Alexandre Guilhem; Nicolas Ricard; Edda Spiekerkoetter; Ruben Hermann; Elisa Rossi; Sabine Bailly; Sophie Dupuis-Girod; Marianne Clancy; Cassi Friday (Angiogenesis, 2025)

Endothelial clock regulates retinal angiogenesis and ganglion cell function - Vijay K. Jidigam; Madison B. Kirby; Joshua Gallop; Brianna M. Shimandle; Dhwani Parsana; Minzhong Yu; Richard A. Lang; Sujata Rao (Angiogenesis, 2025)
Angiogenesis, the formation of new blood vessels from existing ones, is essential for physiological and pathological processes such as wound healing, organ development, and tumor growth. It is a tightly regulated process influenced by both intrinsic and extrinsic factors. Emerging evidence shows a connection between biological clocks that regulate physiological rhythms and angiogenesis through the modulation of angiogenic factors like vascular growth factor (Vegfa). Thus, the clock system can directly modulate the timing and efficiency of angiogenic processes. This study aimed to investigate the role of key circadian clock genes, Bmal1 and Per2, in retinal angiogenesis. Endothelial cell-specific deletion of these genes significantly impairs vessel growth, although distinct phenotypic differences emerge between the two knockout models as angiogenesis progresses. RNA-sequencing (RNA-seq) analysis of retinal endothelial cells reveals that circadian clocks predominantly influence the expression of genes involved in cell proliferation. Notably, vascular endothelial cell (VEC) proliferation is diurnally regulated and is disrupted in Bmal1 knockout animals, leading to an increase in the number of Brn3a-positive retinal ganglion cells (RGCs). These alterations are further associated with compromised retinal circuitry and function. Thus, this study uncovers critical roles for Bmal1 and Per2 in regulating retinal angiogenesis, emphasizing the importance of circadian control of cell proliferation in vascular development and retinal function.

Diverse roles of quaking in endothelial cell biology - Lincy Edatt; Danyan Li; Andrew C. Dudley; Chad V. Pecot (Angiogenesis, 2025)
Quaking (QKI), a member of the signal transduction and activators of RNA (STAR) family of RNA-binding proteins, affects a wide range of functions, including alternative splicing, mRNA precursor processing, mRNA transport and localization, mRNA stabilization, and translation. Recently, QKI has been found to have critical roles in vasculogenesis and angiogenesis due to its effects on alternate splicing and other post-transcriptional modifications involving small RNAs in the endothelial cells (ECs). Aberrant expression or mutation of QKI in ECs can result in pro- or anti-angiogenic effects under different physiological and pathological conditions, including tumor angiogenesis. However, the regulatory roles of QKI in EC biology remain poorly described. This review summarizes our current understanding of the QKI isoforms and their functions in ECs, as well as the potential utility of QKI as an emerging translational target for angiogenic-based therapies.

BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity - Benjamin J. Dunmore; Stephen Moore; Rowena J. Jones; Joshua Hodgson; Kathryn Auckland; Mark Southwood; Nichola Figg; Nobuhiro Kikuchi; Martin Bennett; Allan Lawrie; Christopher J. Rhodes; Mark R. Toshner; et al. (Angiogenesis, 2025)
Deleterious mutations in the GDF2 gene, encoding BMP9, are causative of pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia. Paradoxically, BMP9 germ-line knockout ( Gdf2 −/− ; Bmp9 KO) and double Bmp9 KO / conditional Bmp10 cKO (dKO) mice exhibit an attenuated response to PAH-inducing stimuli. We asked whether this contradiction is due to the pathological, physiological, or genetic consequences of BMP9 knockout. In Bmp9 KO mice we observed reduced pulmonary vascular smooth muscle cell (SMC) coverage and using RNA-seq analysis of Bmp9 KO mouse lungs identified two novel genes, COLQ and ITGA6 , which were differentially regulated in a human PAH RNA-seq dataset. In order to study BMP10 loss, postnatal tamoxifen treatment was required to induce Bmp10 cKO. As previously reported, in dKO mice we observed cardiomegaly and splenomegaly, as well as hyperplasia and hemosiderosis in the pulmonary vasculature. Surprisingly, tamoxifen treated Bmp9 KO control mice phenocopied these pathological changes in dKO mice and downregulated SMC marker gene transcription. Loss of BMP10 is not critical for severe tissue remodelling in the lung, heart, and spleen, rather Bmp9 KO mice appear sensitive to tamoxifen and BMP9 loss is the primary cause of mild vessel remodelling due to a basal reduction of smooth muscle cell coverage. This study suggests that interaction of the BMP pathway with tamoxifen needs to be carefully considered when studying Bmp9 KO mice and urges caution in the context of tamoxifen use when studying cardiovascular and pulmonary disease models.

Multidirectional interstitial flow promotes microvascular network formation: insights from a square chip-based platform - Qihang Yang; Yuening He; Shuo Wang; Zengting Li; Jiaxuan Wang; Zehao Sun; Wenbo Yang; Xiang Zhong; Bo Peng; Zaozao Chen; Zhongze Gu; Dan Zhu; et al. (Angiogenesis, 2025)

IL-8 receptor signaling as a novel target for angiogenic retinopathies - Maximilian J. Garcia; Amanda L. Beall; Monica S. Morales; Nolan J. Beatty; Samuel A. Palmer; Marvarakumari Jhala; Aleksandra Drmanovic; Stephen Priest; Yueli Zhang; Rong Yang; Kyana Arellano; John S. Penn; et al. (Angiogenesis, 2025)
Diabetic retinopathy (DR) is characterized by chronic retinal inflammation and vascular remodeling that can threaten vision. Most current treatments are administered intravitreally and target vascular endothelial growth factor A (VEGF) but are often ineffective. Nevertheless, few alternative treatments, and no oral DR therapies, exist. Although IL-1β, TNFα, and IL-8 are upregulated along with VEGF within eyes with DR, they are not therapeutically targeted. IL-8 levels correlate with DR progression and resistance to anti-VEGF therapy, suggesting VEGF-independent contributions of IL-8-receptor signaling to DR. IL-1β and TNFα, in turn, enhance expression of pro-angiogenic CXCR2 ligands (e.g. IL-8, CXCL1) in human Müller cells (hMC). Despite investigation of CXCR2 roles in several angiogenic and fibrotic diseases, CXCR2 inhibitors have not been explored in DR models. In this study, we show protein upregulation of IL-8 and CXCL1, but no detectable VEGF in conditioned media (CM) from IL-1β and TNFα-stimulated hMC. Stimulation of human retinal microvascular endothelial cells (hRMEC) with this human Müller cell-conditioned media (hMC-CM), as well as directly with IL-8, upregulated hRMEC proliferation and migration. CXCR2 inhibition reduced pro-angiogenic hRMEC responses to hMC-CM and IL-8. Likewise, in vivo, in the oxygen-induced retinopathy (OIR) model, either genetic ( Cxcr2 -/- ) or pharmacologic (SB225002) CXCR2 inhibition reduced pre-retinal neovascularization without altering avascularity or VEGF expression. These findings suggest that: (a) Müller cells may link inflammatory and angiogenic responses in the retina, (b) CXCR2 activation may contribute to DR, and (c) CXCR2 inhibitors may be repurposed to reduce pre-retinal neovascularization, a key feature of proliferative DR.

Revealing the unseen: 3D synchrotron X-Ray imaging of uterine vasculature in adenomyosis - Veerle M. W. Michels; Adam Szmul; Joseph Jacob; Hector Dejea; Bernadette S. de Bakker; Judith A. F. Huirne; Yousif Dawood; Daniël Docter; Lynda J. M. Juffermans; Nicole B. Burger; Richard A. Schoonhoven; Jermo Hanemaaijer - van der Veer; et al. (Angiogenesis, 2025)

Intussusceptive angiogenesis: bridging in vivo and in vitro observations - Steven J. Mentzer; Maximilian Ackermann (Angiogenesis, 2025)

KC1036 in ewing sarcoma: mechanistic insights and future directions for a multi-targeted therapeutic strategy - Du Jiang Yang; Lin Yang; Jiexiang Yang; GuoYou Wang (Angiogenesis, 2025)

Editorial Expression of Concern: The nuclear translocation of endostatin is mediated by its receptor nucleolin in endothelial cells - Nan Song; Yanping Ding; Wei Zhuo; Ting He; Zhiguang Fu; Yang Chen; Xiaomin Song; Yan Fu; Yongzhang Luo (Angiogenesis, 2025)

Zonal endothelial cell heterogeneity underlies murine renal vascular development - Peter M. Luo; Neha H. Ahuja; Christopher Chaney; Danielle Pi; Aleksandra Cwiek; Zaneta Markowska; Chitkale Hiremath; Denise K. Marciano; Karen K. Hirschi; M. Luisa Iruela-Arispe; Thomas J. Carroll; Ondine Cleaver (Angiogenesis, 2025)

Correction: Effects of MDM2 inhibitors on vascular endothelial growth factor-mediated tumor angiogenesis in human breast cancer - Jing Xiong; Qin Yang; Jiansha Li; Sheng Zhou (Angiogenesis, 2025)

Dysfunctional vasculogenesis in adipose-derived stem cells from chronic spinal cord injury patients: implications for autologous cell therapy - DuJiang Yang; Lin Yang; Junjie Chen; Zihe Wang; Shuang Wang; Jiexiang Yang; GuoYou Wang (Angiogenesis, 2025)

Correction: Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation - Timon Kuchler; Roman Günthner; Andrea Ribeiro; Renate Hausinger; Lukas Streese; Anna Wöhnl; Veronika Kesseler; Johanna Negele; Tarek Assali; Javier Carbajo‑Lozoya; Maciej Lech; Heike Schneider; et al. (Angiogenesis, 2025)

Single-cell sequencing insights into the transcriptional landscape of cerebral cavernous malformations - Weiwei Zheng; Liwenyu Chen; Jing Ma; Yuwen Zuo; Suyun Yu; Jia Li; Yin Lu; Yang Zhao (Angiogenesis, 2025)

Myocardial infarction induces endothelial dysfunction with independence of cardiovascular risk factors - Francisco Rafael Jimenez-Trinidad; Núria Solanes; Marta Arrieta; Blanca Llonch; Mercè Roqué; Xavier Freixa; Salvatore Brugaletta; Luis Ortega-Paz; Juan José Rodríguez; Pedro Cepas-Guillen; Gemma Vilhaur; Manel Sabaté; et al. (Angiogenesis, 2025)

Cancer-associated fibroblast-derived SOD3 enhances lymphangiogenesis to drive metastasis in lung adenocarcinoma - May Wathone Oo; Takao Hikita; Tomoha Mashima; Kosuke Torigata; Yin Min Thu; Tomohiro Habu; Hotaka Kawai; Toshiaki Ohara; Shuta Tomida; Sachio Ito; Ken Suzawa; Hitoshi Nagatsuka; et al. (Angiogenesis, 2025)
Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAF SOD3 ), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAF SOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target.

KC1036, a multi-kinase inhibitor with anti-angiogenic activity, can effectively suppress the tumor growth of Ewing sarcoma - Xuejin Ou; Ge Gao; Qizhi Ma; Diyuan Qin; Kai Li; Mingyang Feng; Yu Gao; Yao Zeng; Yue Chen; Xia He; Ting Zhang; Zeming Mo; et al. (Angiogenesis, 2025)

Mitochondrial transfer from adipose-derived regenerative cells contributes therapeutic angiogenesis in a murine hindlimb ischemia model - Yiyang Che; Yuuki Shimizu; Takumi Hayashi; Junya Suzuki; Zhongyue Pu; Kazuhito Tsuzuki; Shingo Narita; Yoshimitsu Yura; Rei Shibata; Toyoaki Murohara (Angiogenesis, 2025)
Objective Adipose-derived regenerative cells (ADRCs) are promising cell sources for damaged tissue regeneration. The efficacy of therapeutic angiogenesis with ADRC implantation in patients with critical limb ischemia has been demonstrated in clinical studies. There are several possible mechanisms in this process such as cytokines and microRNA. Recently, cell-to-cell transfer of mitochondria gains more attention in regenerative medicine. However, the role of the mitochondrial transfer mechanism in ADRCs in the regeneration of functional tissue perfusion following ischemic injury remains unclear. In this study, we aimed to investigate whether mitochondrial transfer is a potential mechanism of therapeutic angiogenesis in ADRCs using a murine hindlimb ischemia model. Methods and results In initial studies, the occurrence of mitochondrial transfer of ADRC to endothelial cells and macrophages in a series of pro-angiogenic effects of ADRC was demonstrated in a mouse model of hindlimb ischemia. Subsequently, we comprehensively elucidated the modes of mitochondrial transfer from ADRCs to HUVECs and macrophages mediated by Connexin43-based gap junctions and tunneling nanotubes using time-lapse confocal microscopy and cell sorting techniques. Furthermore, mitochondrial transfer from ADRCs enhanced mitochondrial biogenesis and angiogenesis in vascular endothelial cells and shifted macrophages toward the M2-phenotype. Notably, partially canceled mitochondrial transfer from ADRCs could impede the angiogenic ability of ADRCs in hind limb ischemia. Conclusions ADRCs can protect against ischemic limbs, at least in part by mitochondrial transfer via gap junctions and tunneling of nanotubes into injured endothelial cells and macrophages. Additionally, mitochondrial transfer is a potential mechanism for therapeutic angiogenesis with ADRCs in hindlimb ischemia. Graphical abstract Schematic illustration showing potential mechanisms of mitochondrial transfer from ADRCs in mouse hindlimb ischemia model. This figure was created with BioRender.

Micropuncture and granular hydrogel scaffolds to surgically bioengineer a perfusable and stably patterned microvasculature - Jessica C. El-Mallah; Zaman Ataie; Summer N. Horchler; Mary E. Landmesser; Mohammad Hossein Asgardoon; Olivia Waldron; Arian Jaberi; Alexander Kedzierski; Mingjie Sun; Amir Sheikhi; Dino J. Ravnic (Angiogenesis, 2025)
Vascularization of implanted biomaterials is critical to reconstructive surgery and tissue engineering. Ultimately, the goal is to promote a rapidly perfusable hierarchical microvasculature that persists with time and can meet underlying tissue needs. We have previously shown that using a microsurgical technique, termed micropuncture (MP), in combination with porous granular hydrogel scaffolds (GHS) fabricated via interlinking hydrogel microparticles (microgels) results in a rapidly perfusable patterned microvasculature. However, whether this engineered microvasculature remains stable at longer time points remains unknown. Here, we combine MP with GHS and compare overall microvascular architecture and phenotype along with the evolving cellular landscape over a 28 day period. We demonstrate perfusable patterned microvascular stability in our MP + GHS model that occurs alongside a sustained rise in endothelial cell and macrophage recruitment. Specifically, MP yields a significant rise in M2 macrophages between the 7 and 28 day time points, suggesting ongoing microvascular remodeling, even in the presence of early pericyte stabilization. With time, the GHS microvasculature acquires a relatively equivalent arterial and venous morphology, as assessed through Ephrin-B2 and EphB4 quantification. Finally, angiography at 28 days shows that MP + GHS is associated with more perfusable microvascular loops when compared with MP + Bulk (nonporous) scaffolds. Hence, our surgically bioengineered microvasculature offers a unique opportunity to sustainably and precisely control biomaterial vascularization and ultimately advance the fields of reconstructive surgery and tissue engineering.

Vasculogenic potential of adipose tissue derived stem cells from patients with chronic spinal cord injury and pressure injuries - Ángela Santos-De-La-Mata; Pedro F. Esteban; Mario Martínez-Torija; Beatriz Paniagua-Torija; Fa. Javier Espino-Rodríguez; Lucía Beltrán-Camacho; Celia Camacho-Toledano; Mónica Alcobendas-Maestro; Fernando García-García; Eduardo Molina-Holgado; Ma Carmen Durán-Ruiz; Juan M. Melero-Martin; et al. (Angiogenesis, 2025)
Limited vascularization and ischemia are major contributors to the chronicity of wounds, such as ulcers and traumatic injuries, which impose significant medical, social, and economic burdens. These challenges are particularly pronounced in patients with spinal cord injury (SCI), a disabling condition associated with vascular dysfunction, infections, and impaired peripheral circulation, complicating the treatment of pressure injuries (PIs) and the success of reconstructive procedures like grafts and flaps. Regenerative medicine aims to address these issues by identifying effective cellular therapies to restore vascular beds. Among these, cells from the stromal vascular fraction (SVF) of adipose tissue (AT) are promising due to their abundance of angiogenic and vasculogenic cells, including mesenchymal stem cells (MSCs) and endothelial colony-forming cells (ECFCs). This study evaluated the vasculogenic potential of AT-derived cellular fractions isolated via enzymatic digestion of white adipose tissue (WAT). We compared adipose-derived stem cells (ASCs) cultured from SVF with a combination of ECFCs and MSCs, expanded separately and transplanted in a 40:60 ratio. Results showed that while ASCs promote angiogenesis and vasculogenesis, the ECFC/MSC combination is superior, consistently forming perfused vascular beds in subcutaneous implants in nude mice. Furthermore, ECFCs and MSCs extracted from small amounts of WAT in SCI patients with PIs demonstrated similar functionality and vasculogenic potential to cells from healthy controls. These findings highlight the potential of AT-derived ECFCs and MSCs in autologous cell therapies, offering a promising avenue for advancing vascular regeneration in patients with SCI.

G3BP1 maintains endothelial barrier integrity through dual mechanisms: direct stabilization of junction protein mRNAs and suppression of the inflammatory MYD88-ARNO-ARF6 pathway - Weiyue Sun; Haoran Wu; Yuxi He; Huiqiao Chen; Yuanhui Meng; Guofang Tang; Jinshun Zhu; Zhengwang Wen; Hui Zhang; Rongzhou Wu; Guowei Wu; Chunxiang Zhang; et al. (Angiogenesis, 2025)

Pathophysiology of endothelial dysfunction in Fontan circulation: from bench to bedside and back again - Amalia Baroutidou; Artemios G. Karagiannidis; Theodoros Dimitroulas; Vasileios Kamperidis; Antonios Ziakas; Konstantinos Dimopoulos; George Giannakoulas (Angiogenesis, 2025)
The Fontan procedure is a definitive surgical approach for complex cardiac malformations, redirecting systemic venous blood into the pulmonary circulation through a staged repair that separates systemic and pulmonary venous returns in the absence of a subpulmonary ventricle. The ensuing unique hemodynamic conditions compromise the endothelial function both in the pulmonary and the systemic circulation. The underlying pathophysiological mechanisms, although distinct within each vascular bed, are interrelated and may collectively contribute to progressive end-organ dysfunction, ultimately accounting for the significant morbidity burden in Fontan patients. This review provides an overview of the current knowledge on the pathophysiology of pulmonary and systemic vasculopathy in Fontan circulation, with particular emphasis on the interplay between endothelial dysfunction and adverse clinical outcomes. Remaining gaps in knowledge and directions of future research are also discussed. Graphical abstract

MY-1 promotes angiogenesis in the ischemic hindlimbs by regulating the stability of CDC42 via PSMD14 - Xian Ding; Yuxin Zhang; Yuting Zeng; Qianlin Li; Sijie Qiu; Ping Xiao; Xin Luo; Jiaping Chen; Qianwen Deng; Dehong Yang; Yanli Zhang; Wenjuan Yan (Angiogenesis, 2025)

UHRF1 in endothelial cells is essential for angiogenesis and associated with the activation of pro-angiogenic signaling pathways and expression of endothelial genes - Ying Liu; Jiake Mo; Zi Guo; Jiaqi Zhang; Weian Tang; Xubiao Meng; Yufang Luo; Fang Wang; Zhaohui Mo (Angiogenesis, 2025)

Angiopoietin-2 binds to FGFR2, inhibits FGF-FGFR2 signaling, and delays cutaneous wound healing by inhibiting wound angiogenesis - Minji Sim; Hidetaka Ohnuki; Stewart Durell; Haydar Bulut; Yuyi Wang; Marzena Dyba; Sergey G. Tarasov; Lisa M. Jenkins; Giovanna Tosato (Angiogenesis, 2025)
Wound healing is an essential repair process, and impaired wound healing is a common and sometimes debilitating medical problem. Despite advances in wound healing approaches, optimal management strategies are lacking, partly due to an incomplete understanding of the complex pathophysiology of this process. Here we show that Ang2, a previously known ligand for the Tie2 receptor, also binds to fibroblast growth factor receptor 2 (FGFR2) independently of Tie2 and attenuates FGF/FGFR2 signaling in endothelial cells. Functionally, Ang2 inhibits endothelial cell migration induced by FGF. In mouse, topical Ang2 delays the healing of skin wounds, associated with reduced wound angiogenesis and recruitment of mesenchymal-type cells. Additionally, topical AMG386, a blocker of Ang1/Ang2 binding to Tie2 and systemic REGN910, a blocker of Ang2 binding to Tie2, accelerate wound repair, associated with increased wound angiogenesis and recruitment of inflammatory cells. These results identify the tyrosine kinase FGFR2 as a previously unrecognized Ang2 receptor, explaining some of the context-dependent functions of Ang2 in endothelial cells. Since Ang2 is induced in cutaneous wounds and endogenous FGF/FGFR2 is essential for wound repair, Ang2 blockade holds promise as a new evidence-based therapeutic option to promote wound repair.

RE: acute aortic dissection in a patient with hereditary hemorrhagic telangiectasia associated with juvenile polyposis due to SMAD4 mutation - Ehab Y. Harahsheh; George Bcharah; Misha B. Asif; Linnea M. Baudhuin; Pavel Pichurin; Fadi Shamoun; Mayowa A. Osundiji (Angiogenesis, 2025)

In vivo profiling of the endothelium using ‘AngioTag’ zebrafish - Mayumi F. Miller; Leah J. Greenspan; Derek E. Gildea; Kathryn Monzo; Gennady Margolin; Van N. Pham; Keith K. Ameyaw; Lisa Price; Natalie Aloi; Amber N. Stratman; Andrew E. Davis; Isabella Cisneros; et al. (Angiogenesis, 2025)
Vascular endothelial cells in vivo are exquisitely regulated by their local environment, which is disrupted or absent when using methods such as FACS sorting of cells isolated from animals or in vitro cell culture. Here, we profile the gene expression patterns of undisturbed endothelial cells in living animals using a novel “AngioTag” zebrafish transgenic line that permits isolation of actively translating mRNAs from endothelial cells in their native environment. This transgenic line uses the endothelial cell-specific kdrl promoter to drive expression of an epitope tagged Rpl10a 60 S ribosomal subunit protein, allowing for Translating Ribosome Affinity Purification (TRAP) of actively translating endothelial cell mRNAs. By performing TRAP-RNAseq on AngioTag animals, we demonstrate strong enrichment of endothelial-specific genes and have uncovered both novel endothelial genes and unique endothelial gene expression signatures for different adult organs. Finally, we generated a versatile “UAS: RiboTag” transgenic line to allow a wider array of different zebrafish cell and tissue types to be examined using TRAP-RNAseq methods. These new tools offer an unparalleled resource to study the molecular identity of cells in their normal in vivo context.

Semaphorin 3A protects against thoracic aortic aneurysm dissection by suppressing aortic angiogenesis - Li-Fei Wu; Jiao-Jiao Zhang; Xing Zhang; De-Ping Wang; Zhi-Fa Zheng; Jing Shen; Ying Zhou; Li-Juan Gao; Xuan Shang; Jun-Ya Ning; Qing-Hua Liu; Lan Zhou; et al. (Angiogenesis, 2025)

Proteoglycans and glycosaminoglycans: critical regulators in angiogenesis, vasculogenesis, and vascularized tissue engineering - Binbin Lin; Tianyu Sun; Yiqi Feng; Hongyu Liu; Lingling Zhang; Buling Wu; Jingyi Wu (Angiogenesis, 2025)

Mechanistic insights into endometriosis: roles of Streptococcus agalactiae and L-carnitine in lesion development and angiogenesis - Yuan Zhuang; Ting Lyu; Yang Chen; Wei Li; Lei Tang; Shi-ping Xian; Peng-fei Yang; Lijie Wang; Qian-qian Zhang; Chaoming Mei; Yu-jing Lin; Zhixiang Yan; et al. (Angiogenesis, 2025)

Endothelial GTPBP3 directs developmental angiogenesis and neovascularization after limb ischemia via the mtROS/HRl/ATF4/mTORC1 axis - Donglu Qin; Jiarui Hu; Yang Yang; Xin Li; Jia He; Jin Chen; Xin Guo; Cheng Wei; Fengjiao Wang; Ting Yi; Chenyu Li; Bilian Yu (Angiogenesis, 2025)

Genetic deletion of microRNA-15a/16-1 in pericytes stimulates cerebral angiogenesis and promotes functional recovery after ischemic stroke - Ping Sun; Yang Xu; Tianqing Xiong; Shun Li; Na Qiu; Chao Zhou; Jiefei Wang; Alexander Chang; Uma R. Chandran; Ke-Jie Yin (Angiogenesis, 2025)

Diversity of extracellular vesicle sources in atherosclerosis: role and therapeutic application - Yuan Zhang; Wendiao Zhang; Zhiwen Wu; Yong Chen (Angiogenesis, 2025)

An endothelial specific mouse model for the capillary malformation mutation Gnaq p.R183Q - Patrick Smits; Leanna Marrs; Yu Sheng Cheng; Michal Ad; Sana Nasim; David Zurakowski; Joyce Bischoff; Arin K. Greene (Angiogenesis, 2025)

High-throughput differentiation of human blood vessel organoids reveals overlapping and distinct functions of the cerebral cavernous malformation proteins - Dariush Skowronek; Robin A. Pilz; Valeriia V. Saenko; Lara Mellinger; Debora Singer; Silvia Ribback; Anja Weise; Kevin Claaßen; Christian Büttner; Emily M. Brockmann; Christian A. Hübner; Thiha Aung; et al. (Angiogenesis, 2025)
Cerebral cavernous malformations (CCMs) are clusters of thin-walled enlarged blood vessels in the central nervous system that are prone to recurrent hemorrhage and can occur in both sporadic and familial forms. The familial form results from loss-of-function variants in the CCM1 , CCM2 , or CCM3 gene. Despite a better understanding of CCM pathogenesis in recent years, it is still unclear why CCM3 mutations often lead to a more aggressive phenotype than CCM1 or CCM2 variants. By combining high-throughput differentiation of blood vessel organoids from human induced pluripotent stem cells (hiPSCs) with a CCM1 , CCM2 , or CCM3 knockout, single-cell RNA sequencing, and high-content imaging, we uncovered both shared and distinct functions of the CCM proteins. While there was a significant overlap of differentially expressed genes in fibroblasts across all three knockout conditions, inactivation of CCM1 , CCM2 , or CCM3 also led to specific gene expression patterns in neuronal, mesenchymal, and endothelial cell populations, respectively. Taking advantage of the different fluorescent labels of the hiPSCs, we could also visualize the abnormal expansion of CCM1 and CCM3 knockout cells when differentiated together with wild-type cells into mosaic blood vessel organoids. In contrast, CCM2 knockout cells showed even reduced proliferation. These observations may help to explain the less severe clinical course in individuals with a pathogenic variant in CCM2 and to decode the molecular and cellular heterogeneity in CCM disease. Finally, the excellent scalability of blood vessel organoid differentiation in a 96-well format further supports their use in high-throughput drug discovery and other biomedical research studies.

Polysialic acid regulates glomerular microvasculature formation by interaction with VEGF-A188 in mice - Kristina M. Niculovic; Manuel M. Vicente; Vanessa Wittek; Elina Kats; Iris Albers; Kerstin Flächsig-Schulz; Ulrike Peters-Bernard; Anna-Carina Weiss; Hauke Thiesler; Laura S. Dräger; Manuel H. Taft; Anne Jörns; et al. (Angiogenesis, 2025)
Vascular endothelial growth factor A (VEGF-A) is a key signalling protein that stimulates blood vessel development and repair. Its tight control is essential for organ development and tissue homeostasis. However, the complex regulatory network for balanced bioavailability of VEGF-A is not fully understood. Here, we assessed the role of the glycocalyx component polysialic acid (polySia) for kidney development and its potential interactions with VEGF-A isoforms, in vitro and in vivo, using mouse models of polySia deficiency. PolySia acts as negative regulator of cell adhesion, but also may interact with extracellular components. In murine kidney, polySia was identified on nephron progenitor and endothelial cell subsets in developing nephrons with declining expression during maturation. Loss of polySia in Ncam −/− mice revealed the neural cell adhesion molecule NCAM as major protein carrier. Both polysialyltransferase-negative and Ncam −/− mice displayed impaired glomerular microvasculature development with reduced endothelial cell numbers, reminiscent to the phenotype of mice with impaired VEGF-A signalling. In vitro, immobilized polySia specifically interacted with the VEGF-A188 isoform demonstrating an isoform-specific direct interaction. Single cell RNA sequencing data analysis of newborn mouse kidneys implicated activation of VEGF-A-signalling in polysialyltransferase-positive endothelial cells. Consistently, loss of polySia resulted in diminished VEGFR2 activation in perinatal kidney and human endothelial cells. At transcriptional level, the expression of polysialyltransferases and known polySia carrier proteins is conserved in human developing kidney. Together, these data demonstrate a direct impact of polySia on VEGF-A signalling with the perspective that polysialylation could be a therapeutic target to ameliorate microvasculature repair after renal injury. Graphical abstract

Human endothelial colony forming cells (ECFCs) require endothelial protein C receptor (EPCR) for cell cycle progression and angiogenic activity - Sarah E. J. Chambers; Jasenka Guduric-Fuchs; Edoardo Pedrini; Pietro M. Bertelli; Chutima Charoensuk; Elisa Peixoto; Varun Pathak; Hamza I. Alhamdan; Ruoxiao Xie; Anna Krasnodembskaya; Judith Lechner; Alan W. Stitt; et al. (Angiogenesis, 2025)
Vascular repair and regeneration are critical for tissue homeostasis. Endothelial colony forming cells (ECFCs) are vessel-resident progenitors with vasoreparative capacity and they offer an important avenue for allogeneic cytotherapy to achieve perfusion of ischemic tissues. Endothelial Protein C Receptor (EPCR) has been proposed as a marker for vascular endothelial stem cells, but its precise role in ECFC biology remains unknown. The current study has investigated the biological relevance of EPCR in ECFC function. Our data show that over 95% of ECFCs exhibit high EPCR expression. These levels surpassing CD34 and CD157, positions EPCR as a new robust ECFC immunophenotypic marker, alongside established markers CD31 and CD105. Functionally, depleting EPCR expression in ECFCs significantly diminished angiogenic activity, including proliferation, migration and tube formation. This knockdown also altered normal ECFC barrier function. Transcriptomic analysis indicated that knockdown of EPCR led to enrichment of gene signatures for cell cycle, TGF beta, and focal adhesion kinases. G1 cell cycle arrest was confirmed in ECFCs with depleted EPCR. Mechanistically, EPCR knockdown led to increased release of TGFβ2 and SMAD2/3 activation, coupled with increased p21, decreased pFAK, and increased transgelin. Additionally, we showed that quiescent ECFCs showed significantly lower EPCR expression when compared to proliferating ECFCs. In agreement with this, cell sorting experiments demonstrated that ECFCs with the highest EPCR expression exhibited the highest clonogenic capacity. In summary, our findings highlight that EPCR expression in ECFCs is critical for their angiogenic activity, by modulating cell cycle progression. Graphical abstract

The VEGF decoy receptor soluble Fms-like tyrosine kinase 1 binds to macrophages - Cleo C. L. van Aanhold; Qing Yong; Lisa Landman; Samiksha Sardana; Anouk B. Bouwmeester; Kyra L. Dijkstra; Ron Wolterbeek; Hailiang Mei; Rayman T. N. Tjokrodirijo; Arnoud H. de Ru; Peter A. van Veelen; Jan A. Bruijn; et al. (Angiogenesis, 2025)
Background Soluble Fms-like Tyrosine kinase-1 (sFLT1) is a native inhibitor of VEGF, best known for its antiangiogenic effects in preeclampsia. sFLT1 also reduces chronic inflammation and promotes tissue repair. In experimental diabetic nephropathy, we previously found that sFLT1 ameliorates kidney fibrosis and reduces the infiltration of macrophages. How sFLT1 regulates inflammation is still incompletely understood. Based on the direct association of sFLT1 with various cell types, we here studied whether sFLT1 interacts with macrophages to modulate inflammation. Methods Using various macrophage cell lines, sFLT1 cell surface binding was detected with flow cytometry. Enzyme studies, mass spectrometry and RNAseq were employed to identify potential sFLT1 cell surface interactors and effects of sFLT1 on macrophage signaling. Results Soluble FLT1 binds to primary macrophages, THP-1 and RAW264.7 macrophages in vitro. Alternative activation with IL-4 increases sFLT1 binding in THP-1 macrophages, whereas proinflammatory activation with IFN-γ and LPS decreases binding. Binding of sFLT1 depends on heparan sulphates, and colocalizes with the membrane heparin sulfate proteoglycan neuropilin-1. Incubation with sFLT1 reduces the gene expression of chemokine receptors. Conclusion Our results show that sFLT1, while typically associated with angiogenesis, also directly interacts with macrophages. Alternative activation of macrophages by IL-4 strongly increases binding of sFLT1 to the cell surface membrane, possibly via the VEGF co-receptor neuropilin-1. Considering sFLT1’s anti-inflammatory effects in animal studies, our findings indicate a novel function for sFLT1 to directly control anti-inflammatory macrophage function.

G protein-coupled receptor GPR182 negatively regulates sprouting angiogenesis via modulating CXCL12-CXCR4 axis signaling - Changsheng Chen; Wei Liu; Fang Yuan; Xiaoning Wang; Xi Xu; Chang Chun Ling; Xiaojuan Ge; Xiaozhong Shen; Bowen Li; Yuqian Shen; Dong Liu (Angiogenesis, 2025)
Angiogenesis is a critical process for tumor progression, regulated by various signaling pathways. Although antiangiogenic therapies targeting the VEGF pathway have shown potential, their effectiveness is inconsistent across different tumor types. GPR182, an endothelial cell-specific G protein-coupled receptor, is frequently downregulated in hypervascular tumors, but its specific role in angiogenesis has not been well defined. Our study reveals that GPR182 expression is markedly reduced in hepatocellular carcinoma (HCC) and inversely correlates with CD31, a pan-endothelial marker. In zebrafish embryos, Gpr182 deficiency resulted in enhanced angiogenic sprouting and hypervascularization, and GPR182-deficient human umbilical vein endothelial cells (HUVECs) showed increased migration and proliferation. At the molecular level, GPR182 acts as a decoy receptor, binding CXCL12 and regulating its gradient, which in turn suppresses CXCR4-mediated angiogenesis. The pharmacological blockade of CXCR4 with AMD3100 corrected the abnormal angiogenic phenotype in Gpr182-deficient zebrafish embryos and in the livers of a zebrafish HCC model. This work uncovers GPR182 as a negative regulator of angiogenesis, a key process in tumor growth and metastasis, and proposes that targeting GPR182 may offer a novel therapeutic approach for antiangiogenic strategies in cancer treatment.

Mixed lineage kinase (MLK) controls tumor development and angiogenesis - Shashi Kant; Amada D. Caliz; Hyung-Jin Yoo; Gaganpreet Kaur; Heather Learnard; Hassan A. Khalil; Roger J. Davis; John F. Keaney (Angiogenesis, 2025)

SDF-1α mRNA therapy in peripheral artery disease - Tinghong Zhang; Binqiang Zhu; Shijie Deng; Jinling Qin; Jingyuan Zhang; Shu Meng (Angiogenesis, 2025)
Stromal cell-derived factor-1 alpha (SDF-1α) is a promising target for therapeutic angiogenesis in ischemic diseases such as peripheral artery disease (PAD). However, the clinical application of SDF-1α protein or plasmid-based gene therapy is unsuccessful. mRNA therapy has shown great promise in protein replacement. Here, we developed DOPE-lipid nanoparticles (LNPs) encapsulating SDF-1α mRNA (LNP@SDF-1α) for efficient gene delivery. In vitro, LNP@SDF-1α treatment of human umbilical vein endothelial cells (HUVECs) significantly enhanced endothelial migration, tube formation, and increased monocyte adhesion, demonstrating robust pro-angiogenic activity. In vivo, LNP@SDF-1α transfected HUVECs showed enhanced angiogenic capacity in a murine Matrigel plug model. Furthermore, in a mouse hindlimb ischemia model, intramuscular injection of LNP@SDF-1α into ischemic limbs accelerated blood flow recovery, as assessed by laser speckle contrast imaging. Immunofluorescence staining revealed a marked increase in capillary and arteriole densities in treated tissues. Angiogenic protein profiling demonstrated an upregulation of pro-angiogenic factors, including VEGF and Ang-1, and a downregulation of anti-angiogenic factors. No significant toxicity was observed in major organs, indicating the safety of this approach. Our study demonstrates that SDF-1α mRNA therapy, delivered via DOPE-LNPs, significantly promotes vascular regeneration in ischemic tissues by enhancing angiogenesis and arteriogenesis, thereby restoring blood perfusion. This approach presents a promising therapeutic option for PAD and suggests broader applications of mRNA-based therapies for ischemic diseases.

Acute aortic dissection in a patient with Hereditary Hemorrhagic Telangiectasia associated with Juvenile Polyposis due to SMAD4 mutation: case report and literature review - Catalina Pezzoto; Ana Braslavsky; Carolina Vázquez; Candelaria Serrano; Marcelo Serra (Angiogenesis, 2025)

ApoM-bound S1P acts via endothelial S1PR1 to suppress choroidal neovascularization and vascular leakage - Bongnam Jung; Hitomi Yagi; Andrew Kuo; Tim F. Dorweiler; Masanori Aikawa; Taku Kasai; Sasha A. Singh; Andrew J. Dannenberg; Zhongjie Fu; Colin Niaudet; Lois E. H. Smith; Timothy Hla (Angiogenesis, 2025)

Endothelial USP11 drives VEGFR2 signaling and angiogenesis via PRDX2/c-MYC axis - Can Chen; Zilong Chen; Ruijie Luo; Wanheng Tu; Minwen Long; Minglu Liang; Min Cheng; Zhaohui Wang; Kai Huang; Cheng Wang (Angiogenesis, 2025)

Microvascular and cerebrovascular alterations in Raynaud’s phenomenon and fibromyalgia - Angelo Nigro (Angiogenesis, 2025)

Endothelial transcriptomic, epigenomic and proteomic data challenge the proposed role for TSAd in vascular permeability - James T. Brash; Guillermo Diez-Pinel; Luca Rinaldi; Raphael F. P. Castellan; Alessandro Fantin; Christiana Ruhrberg (Angiogenesis, 2025)
The vascular endothelial growth factor VEGF drives excessive vascular permeability to cause tissue-damaging oedema in neovascular and inflammatory diseases across multiple organs. Several molecular pathways have been implicated in VEGF-induced hyperpermeability, including binding of the VEGF-activated tyrosine kinase receptor VEGFR2 by the T-cell specific adaptor (TSAd) to recruit a SRC family kinase to induce junction opening between vascular endothelial cells (ECs). Inconsistent with a universal role for TSAd in permeability signalling, immunostaining approaches previously reported TSAd only in dermal and kidney vasculature. To address this discrepancy, we have mined publicly available omics data for expression of TSAd and other permeability-relevant signal transducers in multiple organs affected by VEGF-induced vascular permeability. Unexpectedly, TSAd transcripts were largely absent from EC single cell RNAseq data, whereas transcripts for other permeability-relevant signal transducers were detected readily. TSAd transcripts were also lacking from half of the EC bulk RNAseq datasets examined, and in the remaining datasets appeared at low levels concordant with models of leaky transcription. Epigenomic EC data located the TSAd promoter to closed chromatin in ECs, and mass spectrometry-derived EC proteomes typically lacked TSAd. By suggesting that TSAd is not actively expressed in ECs, our findings imply that TSAd is likely not critical for linking VEGFR2 to downstream signal transducers for EC junction opening.

Isolated human adipose microvessels retain native microvessel structure and recapitulate sprouting angiogenesis - Sarah M. Moss; Thomas Gerton; Hannah A. Strobel; James B. Hoying (Angiogenesis, 2025)

Immune-privileged cord blood-derived endothelial colony-forming cells: advancing immunomodulation and vascular regeneration - David M. Smadja; Yanis Berkane; Nun K. Bentounes; Jeanne Rancic; Audrey Cras; Cécile Pinault; Marie Ouarne; Elise Paucod; Walid Rachidi; Alexandre G. Lellouch; Maxime Jeljeli (Angiogenesis, 2025)
Cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold significant promise for regenerative medicine due to their unique vasculogenic and immunomodulatory properties. These cells exhibit a superior proliferative capacity, robust ability to form vascular networks, and lower immunogenicity compared to adult and embryonic stem cell-derived counterparts. The immune-privileged characteristics of CB-ECFCs, including reduced expression of pro-inflammatory mediators and tolerance-inducing molecules such as HLA-G, further enhance their therapeutic potential. Their low immunogenicity minimizes the risk of immune rejection, making them suitable for allogenic cell therapies. Their application extends to complex tissue engineering and organ revascularization, where their ability to integrate into three-dimensional scaffolds and support vascular tree formation represents a significant advancement. Moreover, CB-ECFCs’ capability to adapt to inflammatory stimuli and retain immunological memory highlights their functional versatility in dynamic microenvironments. This review highlights the remarkable ontogeny of ECFCs while unveiling the unparalleled potential of CB-ECFCs in revolutionizing regenerative medicine. From pre-vascularizing engineered tissues and organoids to pioneering cell-based therapies for cardiovascular, dermatological, and degenerative diseases, CB-ECFCs stand at the forefront of cutting-edge biomedical advancements, offering unprecedented opportunities for therapeutic innovation. By leveraging their vasculogenic, immune-regulatory, and regenerative capacities, CB-ECFCs offer a robust alternative for addressing the challenges of vascular repair and organ engineering. Future research should focus on unraveling their transcriptomic and functional profiles to optimize clinical applications and advance the field of regenerative medicine.

Correction: CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation - Ting-Ting Chang; Liang-Yu Lin; Ching Chen; Jaw-Wen Chen (Angiogenesis, 2025)

Cxcl9 modulates aging associated microvascular metabolic and angiogenic dysfunctions in subcutaneous adipose tissue - Xin Fu; Yu Zhao; Xiwei Cui; Siyuan Huang; Yanze Lv; Chen Li; Fuxing Gong; Zhigang Yang; Xiaonan Yang; Ran Xiao (Angiogenesis, 2025)

Correction: Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions - Sagnik Pal; Yangyang Su; Emmanuel Nwadozi; Lena Claesson-Welsh; Mark Richards (Angiogenesis, 2025)

From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations - Ashely R. Ricciardelli; Gael Genet; Nafiisha Genet; Samuel T. McClugage; Peter T. Kan; Karen K. Hirschi; Jason E. Fish; Joshua D. Wythe (Angiogenesis, 2025)
Brain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in the RAS-MAPK signaling pathway. Leveraging these genetic discoveries, preclinical mouse models have been developed to uncover the mechanisms underlying abnormal vessel formation, and thus revealing potential therapeutic targets. Impressively, initial preclinical studies suggest that pharmacological treatments disrupting these aberrant pathways may ameliorate the abnormal pathologic vessel remodeling and inflammatory and hemorrhagic nature of these high-flow vascular anomalies. Intriguingly, these studies also suggest uncontrolled angiogenic signaling may be a major driver in bAVM pathogenesis. This comprehensive review describes the genetics underlying both inherited and sporadic bAVM and details the state of the field regarding murine models of bAVM, highlighting emerging therapeutic targets that may transform our approach to treating these devastating lesions.

The role of liver sinusoidal endothelial cells in metabolic dysfunction-associated steatotic liver diseases and liver cancer: mechanisms and potential therapies - Hanjun Mo; Pengfei Yue; Qiaoqi Li; Yinxi Tan; Xinran Yan; Xinyue Liu; Yuanwei Xu; Yingzhe Luo; Suruiya Palihati; Cheng Yi; Hua Zhang; Minlan Yuan; et al. (Angiogenesis, 2025)

Clioquinol inhibits angiogenesis by promoting VEGFR2 degradation and synergizes with AKT inhibition to suppress triple-negative breast cancer vascularization - Yuan Gu; Tianci Tang; Moqin Qiu; Hongmei Wang; Emmanuel Ampofo; Michael D. Menger; Matthias W. Laschke (Angiogenesis, 2025)
Inhibition of angiogenesis, either as monotherapy or in conjunction with other treatments, holds significant promise in cancer treatment. However, the limited efficacy of clinically approved anti-angiogenic agents underscores the urgent need for the development of novel drugs and therapeutic strategies. In this study, we demonstrate the highly selective inhibitory effects of clioquinol, a topical antifungal and antibiotic agent, on the angiogenic activity of endothelial cells (ECs) in a series of in vitro angiogenesis assays. Moreover, clioquinol effectively suppressed blood vessel formation in ex vivo aortic ring and in vivo Matrigel plug assays. Mechanistic studies revealed that clioquinol directly binds to the ATP-binding site of vascular endothelial growth factor receptor 2 (VEGFR2), promoting its degradation through both proteasome and lysosome pathways. This led to the down-regulation of the downstream extracellular signal-regulated kinase (ERK) pathway. In addition, the combination with the AKT inhibitor MK-2206 synergistically boosted the anti-angiogenic efficacy of clioquinol in vitro and in an in vivo dorsal skinfold chamber model of triple-negative breast cancer (TNBC), leading to the suppression of TNBC growth. Accordingly, clioquinol, either alone or in combination with AKT inhibitors, represents a promising therapeutic agent for future anti-angiogenic cancer treatment.

Anti-angiogenic therapy as potential treatment for adenomyosis - Marissa J. Harmsen; Lynda J. M. Juffermans; Muara O. Kroon; Arjan W. Griffioen; Judith A. F. Huirne (Angiogenesis, 2025)
Adenomyosis is characterized by abnormal uterine bleeding, dysmenorrhea and subfertility. Increased expression of angiogenesis markers in adenomyosis presents a treatment opportunity and was studied in an adenomyosis mouse model. Mice were administered tamoxifen (1 mg/kg) on neonatal days 2–5. At six weeks of age, mice received oral treatment with axitinib 3 mg/kg (‘dose I/AX3’, n = 34), axitinib 25 mg/kg (‘dose II/AX25’ n = 34), or with vehicle-only (‘placebo’, n = 34). The prevalence and severity of adenomyosis were assessed. An adenomyosis severity index was calculated by multiplying mean grade/mouse by the percentage affected surface area. Angiogenesis-related gene expression was evaluated using real-time quantitative PCR. 101 mice completed adenomyosis induction and could be analyzed. The prevalence of adenomyosis was 30/33 (90.0%) in dose I, 29/34 (85.3%) in dose II, and 30/34 (88.2%) in placebo treated mice (p = 0.78). High grade (2/3) adenomyosis was significantly less prevalent in mice treated with axitinib dose II (n = 19, 55.9%) than in the placebo group (n = 27, 79.4%, p

Ref-1 is overexpressed in neovascular eye disease and targetable with a novel inhibitor - Anbukkarasi Muniyandi; Gabriella D. Hartman; Kamakshi Sishtla; Ratan Rai; Cátia Gomes; Kristina Day; Yang Song; Andi R. Masters; Sara K. Quinney; Xiaoping Qi; Hailey Woods; Michael E. Boulton; et al. (Angiogenesis, 2025)

A novel quantitative angiogenesis assay based on visualized vascular organoid - Yun Zhao; Mengze Sun; Zihang Pan; Weijing Kong; Zixuan Hong; Wei Zhang; Bingbing Sun; Jingjing Zhang; Xi Wang; Kai Wang (Angiogenesis, 2025)

Effect of oral nintedanib vs placebo on epistaxis in hereditary hemorrhagic telangiectasia: the EPICURE multicenter randomized double-blind trial - Ruben Hermann; Vincent Grobost; Xavier Le-Guillou; Christian Lavigne; Antoine Parrot; Sophie Rivière; Julie Séguier; Anne-Emmanuelle Fargeton; Aurélie de-Montigny; Margaux Huot; Evelyne Decullier; Adeline Roux; et al. (Angiogenesis, 2025)
Epistaxis greatly affects patients with hereditary hemorrhagic telangiectasia (HHT). Although few systemic treatment exist, nintedanib, is a good candidate thanks to its anti-angiogenic activity. Our main objective was to evaluate the efficacy of oral nintedanib on epistaxis duration in HHT patients with moderate to severe epistaxis. This multicenter phase 2 randomized, placebo-controlled, double-blind trial was conducted between June 2020 and February 2023. Inclusion criteria were being over 18 years old and having a confirmed HHT diagnosis with an epistaxis severity score greater than 4. Sixty patients were randomized to receive either nintedanib or placebo for 12 weeks with a 12 week follow-up. The primary endpoint was the proportion of patients achieving a reduction of at least 50% in mean monthly epistaxis duration comparing the 8 weeks before treatment to the last 8 weeks of treatment. Main secondary outcomes included monthly duration and frequency of epistaxis and hemoglobin levels. Of the 60 randomized patients, 56 completed the trial. Thirteen patients (43%) in the nintedanib group vs 8 (27%) in the placebo group met the primary endpoint ( p = 0.28). We observed a significant decrease in median epistaxis (57% vs 27%, p = 0.013) and a significant increase in median hemoglobin levels (+ 18 vs − 1 g/L, p = 0.02) in the nintedanib vs the placebo group. Although we did not achieve our primary outcome, we observed a significant reduction in epistaxis duration and a significant increase in hemoglobin levels in patients treated with nintedanib. This supports the efficacy of nintedanib, and further studies are needed.

Circulating endothelial cells: a key biomarker of persistent fatigue after hospitalization for COVID-19 - David M. Smadja; Sven Günther; Pauline Cavagna; Bertrand Renaud; Dominique Salmon; Bertrand Hermann; Brigitte Ranque; Cédric Lemogne; Jean-Luc Diehl; Aurélien Philippe (Angiogenesis, 2025)

Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions - Sagnik Pal; Yangyang Su; Emmanuel Nwadozi; Lena Claesson-Welsh; Mark Richards (Angiogenesis, 2025)
Neuropilin-1 (NRP1) regulates endothelial cell (EC) biology through modulation of vascular endothelial growth factor receptor 2 (VEGFR2) signalling by presenting VEGFA to VEGFR2. How NRP1 impacts VEGFA-mediated vascular hyperpermeability has however remained unresolved, described as exerting either a positive or a passive function. Using EC-specific Nrp1 knock-out mice, we discover that EC-expressed NRP1 exerts an organotypic role. In the ear skin, VEGFA/VEGFR2-mediated vascular leakage was increased following loss of EC NRP1, implicating NRP1 in negative regulation of VEGFR2 signalling. In contrast, in the back skin and trachea, loss of EC NRP1 decreased vascular leakage. In accordance, phosphorylation of vascular endothelial (VE)-cadherin was increased in the ear skin but suppressed in the back skin of Nrp1 iECKO mice. NRP1 expressed on perivascular cells has been shown to impact VEGF-mediated VEGFR2 signalling. Importantly, expression of NRP1 on perivascular cells was more abundant in the ear skin than in the back skin. Global loss of NRP1 resulted in suppressed VEGFA-induced vascular leakage in the ear skin, implicating perivascular NRP1 as a juxtacrine co-receptor of VEGFA in this compartment. Altogether, we demonstrate that perivascular NRP1 is an active participant in EC VEGFA/VEGFR2 signalling and acts as an organotypic modifier of EC biology.

Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT - Antonio Queiro-Palou; Yi Jin; Lars Jakobsson (Angiogenesis, 2025)
Arteriovenous malformations (AVMs) are abnormal high flow shunts between arteries and veins with major negative impact on the cardiovascular system. Inherited loss-of-function (LOF) mutations in endoglin, encoding an endothelial cell (EC) expressed co-receptor for BMP9/10, causes the disease HHT1/Osler-Weber-Rendu, characterized by bleeding and AVMs. Here we observe increased activity of the downstream signalling complex mTORC1 within the retinal vasculature of HHT mouse models. To investigate its importance in AVM biology, concerning subvascular action, cell specificity, signalling strength and kinetics we combine timed genetic and antibody-based models of HHT with genetic mTORC1 inhibition or activation through EC specific deletion of Rptor or Tsc1 . Results demonstrate that EC mTORC1 activation is secondary to endoglin LOF and mainly a consequence of systemic effects following AVM. While genetic EC inhibition of mTORC1 only showed tendencies towards reduced AVM severity, EC overactivation counterintuitively reduced it, implying that mTORC1 must be within a certain range to facilitate AVM. Complete inhibition of mTORC1 signalling by rapamycin provided the strongest therapeutic effect, pointing to potential involvement of RAPTOR-independent pathways or AVM-promoting effects of non-ECs in this pathology.

Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues - Zeenat Diwan; Jia Kang; Emma Tsztoo; Arndt F. Siekmann (Angiogenesis, 2025)
Hemodynamic cues are thought to control blood vessel hierarchy through a shear stress set point, where flow increases lead to blood vessel diameter expansion, while decreases in blood flow cause blood vessel narrowing. Aberrations in blood vessel diameter control can cause congenital arteriovenous malformations (AVMs). We show in zebrafish embryos that while arteries behave according to the shear stress set point model, veins do not. This behavior is dependent on distinct arterial and venous endothelial cell (EC) shapes and sizes. We show that arterial ECs enlarge more strongly when experiencing higher flow, as compared to vein cells. Through the generation of chimeric embryos, we discover that this behavior of vein cells depends on the bone morphogenetic protein (BMP) pathway components Endoglin and Alk1. Endoglin ( eng ) or alk1 ( acvrl1 ) mutant vein cells enlarge when in normal hemodynamic environments, while we do not observe a phenotype in either acvrl1 or eng mutant ECs in arteries. We further show that an increase in vein diameters initiates AVMs in eng mutants, secondarily leading to higher flow to arteries. These enlarge in response to higher flow through increasing arterial EC sizes, fueling the AVM. This study thus reveals a mechanism through which BMP signaling limits vein EC size increases in response to flow and provides a framework for our understanding of how a small number of mutant vein cells via flow-mediated secondary effects on wildtype arterial ECs can precipitate larger AVMs in disease conditions, such as hereditary hemorrhagic telangiectasia (HHT).

Inhibition of Angiopoietin-2 rescues sporadic brain arteriovenous malformations by reducing pericyte loss - Tianqi Tu; Shikun Zhang; Jingwei Li; Chendan Jiang; Jian Ren; Shiju Zhang; Xiaosheng Meng; Hao Peng; Dong Xing; Hongqi Zhang; Tao Hong; Jiaxing Yu (Angiogenesis, 2025)

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) drives abnormal pericyte-rich vasculature in triple-negative breast cancer - Marianna Moro; Federica Carolina Balestrero; Giorgia Colombo; Simone Torretta; Nausicaa Clemente; Valerio Ciccone; Erika Del Grosso; Sandra Donnini; Cristina Travelli; Fabrizio Condorelli; Sabina Sangaletti; Armando A. Genazzani; et al. (Angiogenesis, 2025)

Study on mitogenic activity of serum from patients with total coronary occlusions: relation to duration of occlusion - V. Tchaikovski; G. S. Werner; M. Fritzenwanger; E. Jandt; Johannes Waltenberger (Angiogenesis, 2025)
In contrast to the extensive evidence from animal studies, only few human data are available on the relation of vascular growth factors and collateral function as well as on the conditions which may modify their release or function. In 31 patients with total coronary occlusion (TCOs) blood was collected from distal to the occlusion site (collateral circulation) and from the aortic root (systemic circulation). Serum was used to assess its mitogenic potential in [ 3 H]-thymidine incorporation assay on human umbilical vein endothelial cells. Serum from patients with the duration of occlusion between 1 and 3 months was significantly more mitogenic as compared to either shorter or longer duration of occlusion. None of the demographic or clinical factors correlated with the mitogenic activity of serum. Serum from patients with TCOs shows a particular time-dependent mitogenic profile with a maximal activity between 1 and 3 months following the occlusion. This profile corresponds to the experimentally described time-line of strongest collateral development and indicates the time-window for possible modification.

Retinal pigment epithelial cells reduce vascular leak and proliferation in retinal neovessels - Simone Tzaridis; Edith Aguilar; Michael I. Dorrell; Martin Friedlander; Kevin T. Eade (Angiogenesis, 2025)
In multiple neurodegenerative diseases, including age-related macular degeneration, retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), retinal pigment epithelial (RPE)-cells proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Though these pigmentary changes are hallmarks of disease progression, it is unknown if their presence is protective or detrimental. Here, we first evaluated the impact of pigment plaques on vascular changes and disease progression in MacTel. In a retrospective, longitudinal study, we analyzed multimodal retinal images of patients with MacTel and showed that pigment plaques were associated with decreased vascular leakage and stabilized neovascular growth. We then modeled the underlying pathomechanisms of pigment plaque formation in aberrant neovascular growth using the very-low-density lipoprotein receptor mutant ( Vldlr −/− ) mouse. Our data indicated that during RPE-proliferation, migration and accumulation along neovessels RPE-cells underwent epithelial-mesenchymal transition (EMT). Pharmacologic inhibition of EMT in Vldlr −/− mice decreased pigment coverage, and exacerbated neovascular growth and vascular leakage. Our findings indicate that the proliferation, migration and perivascular accumulation of RPE-cells stabilize vascular proliferation and exudation, thereby exerting a protective effect on the diseased retina. We conclude that interfering with this “natural repair mechanism” may have detrimental effects on the course of the disease and should thus be avoided.

Correction: Mitochondrial control of hypoxia-induced pathological retinal angiogenesis - Hitomi Yagi; Myriam Boeck; Shen Nian; Katherine Neilsen; Chaomei Wang; Jeff Lee; Yan Zeng; Matthew Grumbine; Ian R. Sweet; Taku Kasai; Kazuno Negishi; Sasha A. Singh; et al. (Angiogenesis, 2024)

Angiogenesis is limited by LIC1-mediated lysosomal trafficking - Dymonn Johnson; Sarah Colijn; Jahmiera Richee; Joseph Yano; Margaret Burns; Andrew E. Davis; Van N. Pham; Amra Saric; Akansha Jain; Ying Yin; Daniel Castranova; Mariana Melani; et al. (Angiogenesis, 2024)

Similarities and differences between brain and skin GNAQ p.R183Q driven capillary malformations - Sana Nasim; Colette Bichsel; Anna Pinto; Sanda Alexandrescu; Harry Kozakewich; Joyce Bischoff (Angiogenesis, 2024)

Inflammasome activation aggravates choroidal neovascularization - Ryan D. Makin; Ivana Apicella; Roshni Dholkawala; Shinichi Fukuda; Shuichiro Hirahara; Yoshio Hirano; Younghee Kim; Ayami Nagasaka; Yosuke Nagasaka; Siddharth Narendran; Felipe Pereira; Akhil Varshney; et al. (Angiogenesis, 2024)
Inflammasome activation is implicated in diseases of aberrant angiogenesis such as age-related macular degeneration (AMD), though its precise role in choroidal neovascularization (CNV), a characteristic pathology of advanced AMD, is ill-defined. Reports on inhibition of inflammasome constituents on CNV are variable and the precise role of inflammasome in mediating pathological angiogenesis is unclear. Historically, subretinal injection of inflammasome agonists alone has been used to investigate retinal pigmented epithelium (RPE) degeneration, while the laser photocoagulation model has been used to study pathological angiogenesis in a model of CNV. Here, we report that the simultaneous introduction of any of several disease-relevant inflammasome agonists ( Alu or B2 RNA, Alu cDNA, or oligomerized amyloid β (1–40)) exacerbates laser-induced CNV. These activities were diminished or abrogated by genetic or pharmacological targeting of inflammasome signaling constituents including P2rx7, Nlrp3, caspase-1, caspase-11, and Myd88, as well as in myeloid-specific caspase-1 knockout mice. Alu RNA treatment induced inflammasome activation in macrophages within the CNV lesion, and increased accumulation of macrophages in an inflammasome-dependent manner. Finally, IL-1β neutralization prevented inflammasome agonist-induced chemotaxis, macrophage trafficking, and angiogenesis. Collectively, these observations support a model wherein inflammasome stimulation promotes and exacerbates CNV and may be a therapeutic target for diseases of angiogenesis such as neovascular AMD.

Timed topical dexamethasone eye drops improve mitochondrial function to prevent severe retinopathy of prematurity - Hitomi Yagi; Myriam Boeck; Mariya Petrishka-Lozenska; Pia Lundgren; Taku Kasai; Gael Cagnone; Katherine Neilsen; Chaomei Wang; Jeff Lee; Yohei Tomita; Sasha A. Singh; Jean-Sébastien Joyal; et al. (Angiogenesis, 2024)
Pathological neovascularization in retinopathy of prematurity (ROP) can cause visual impairment in preterm infants. Current ROP treatments which are not preventative and only address late neovascular ROP, are costly and can lead to severe complications. We showed that topical 0.1% dexamethasone eye drops administered prior to peak neovessel formation prevented neovascularization in five extremely preterm infants at high risk for ROP and suppressed neovascularization by 30% in mouse oxygen-induced retinopathy (OIR) modeling ROP. In contrast, in OIR, topical dexamethasone treatment before any neovessel formation had limited efficacy in preventing later neovascularization, while treatment after peak neovessel formation had a non-statistically significant trend to exacerbating disease. Optimally timed topical dexamethasone suppression of neovascularization in OIR was associated with increased retinal mitochondrial gene expression and decreased inflammatory marker expression, predominantly found in immune cells. Blocking mitochondrial ATP synthetase reversed the inhibitory effect of dexamethasone on neovascularization in OIR. This study provides new insights into topical steroid effects in retinal neovascularization and into mitochondrial function in phase II ROP, and suggests a simple clinical approach to prevent severe ROP.

The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP - Zhengrong Zhang; Weiwei Lin; Qini Gan; Maohua Lei; Bin Gong; Chao Zhang; Jessica Salles Henrique; Jingyan Han; Hua Tian; Qiushan Tao; Lawrence A. Potempa; Thor D. Stein; et al. (Angiogenesis, 2024)

Oscillatory contractile forces refine endothelial cell-cell interactions for continuous lumen formation governed by Heg1/Ccm1 - Jianmin Yin; Ludovico Maggi; Cora Wiesner; Markus Affolter; Heinz-Georg Belting (Angiogenesis, 2024)
The formation and organization of complex blood vessel networks rely on various biophysical forces, yet the mechanisms governing endothelial cell-cell interactions under different mechanical inputs are not well understood. Using the dorsal longitudinal anastomotic vessel (DLAV) in zebrafish as a model, we studied the roles of multiple biophysical inputs and cerebral cavernous malformation (CCM)-related genes in angiogenesis. Our research identifies heg1 and krit1 ( ccm1 ) as crucial for the formation of endothelial cell-cell interfaces during anastomosis. In mutants of these genes, cell-cell interfaces are entangled with fragmented apical domains. A Heg1 live reporter demonstrated that Heg1 is dynamically involved in the oscillatory constrictions along cell-cell junctions, whilst a Myosin live reporter indicated that heg1 and krit1 mutants lack actomyosin contractility along these junctions. In wild-type embryos, the oscillatory contractile forces at junctions refine endothelial cell-cell interactions by straightening junctions and eliminating excessive cell-cell interfaces. Conversely, in the absence of junctional contractility, the cell-cell interfaces become entangled and prone to collapse in both mutants, preventing the formation of a continuous luminal space. By restoring junctional contractility via optogenetic activation of RhoA, contorted junctions are straightened and disentangled. Additionally, haemodynamic forces complement actomyosin contractile forces in resolving entangled cell-cell interfaces in both wild-type and mutant embryos. Overall, our study reveals that oscillatory contractile forces governed by Heg1 and Krit1 are essential for maintaining proper endothelial cell-cell interfaces and thus for the formation of a continuous luminal space, which is essential to generate a functional vasculature.

Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability - Hui Feng; Liang Liang; Wenli Deng; Jiaojiao Gao; Xiang Li; Feng Guan (Angiogenesis, 2024)

Senescent endothelial cells: a potential target for diabetic retinopathy - Ying-Lu Liao; Yi-Fan Fang; Jia-Xing Sun; Guo-Rui Dou (Angiogenesis, 2024)

Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications - Layal EI Wazan; Ariel Widhibrata; Guei-Sheung Liu (Angiogenesis, 2024)

The angiogenic role of the alpha 9-nicotinic acetylcholine receptor in triple-negative breast cancers - Sonjid Ochirbat; Tzu-Chun Kan; Chun-Chun Hsu; Tzu-Hsuan Huang; Kuo-Hsiang Chuang; Michael Chen; Chun-Chia Cheng; Chun-Chao Chang; Sri Rahayu; Jungshan Chang (Angiogenesis, 2024)

Maternal serum PlGF associates with 3D power doppler ultrasound markers of utero-placental vascular development in the first trimester: the rotterdam periconception cohort - Eline S. de Vos; A. H. Jan Danser; Anton H. J. Koning; Sten P. Willemsen; Lotte E. van der Meeren; Eric. A. P. Steegers; Régine P. M. Steegers-Theunissen; Annemarie G. M. G. J. Mulders (Angiogenesis, 2024)
Objective (s) Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature. Methods In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7–9–11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm 3 . The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories. Results Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values Conclusion(s) Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854.

PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer - Die Yu; Hanzheng Xu; Jinzhe Zhou; Kai Fang; Zekun Zhao; Ke Xu (Angiogenesis, 2024)

Mitochondrial control of hypoxia-induced pathological retinal angiogenesis - Hitomi Yagi; Myriam Boeck; Shen Nian; Katherine Neilsen; Chaomei Wang; Jeff Lee; Yan Zeng; Matthew Grumbine; Ian R. Sweet; Taku Kasai; Kazuno Negishi; Sasha A. Singh; et al. (Angiogenesis, 2024)
Objective Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization. Methods OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome changes and the ratio of mitochondrial to nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented to OIR mice either prior to or during neovessel formation. Results In OIR vs. control retinas, global proteomics showed decreased retinal mitochondrial respiration at peak neovascularization. OCR and mtDNA/nDNA were also decreased at peak neovascularization suggesting impaired mitochondrial respiration. In vivo pyruvate administration during but not prior to neovessel formation (in line with mitochondrial activity time course) suppressed NV. Conclusions Mitochondrial energetics were suppressed during retinal NV in OIR. Appropriately timed supplementation of pyruvate may be a novel approach in neovascular retinal diseases.

Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction - Boxian Pang; Guangtong Dong; Tieliang Pang; Xinyao Sun; Xin Liu; Yifeng Nie; Xing Chang (Angiogenesis, 2024)
As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for “energy information transfer,” can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.

A streamlined method to generate endothelial cells from human pluripotent stem cells via transient doxycycline-inducible ETV2 activation - Allen Chilun Luo; Jiuhai Wang; Kai Wang; Yonglin Zhu; Liyan Gong; Umji Lee; Xiang Li; Daniel M. Tremmel; Ruei-Zeng Lin; Donald E. Ingber; James Gorman; Juan M. Melero-Martin (Angiogenesis, 2024)

Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition - Friedrich G. Kapp; Farhad Bazgir; Nagi Mahammadzade; Mehrnaz Mehrabipour; Erik Vassella; Sarah M. Bernhard; Yvonne Döring; Annegret Holm; Axel Karow; Caroline Seebauer; Natascha Platz Batista da Silva; Walter A. Wohlgemuth; et al. (Angiogenesis, 2024)
Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

Site-specific genetic and functional signatures of aortic endothelial cells at aneurysm predilection sites in healthy and AngII ApoE−/− mice - Alexander Brückner; Adrian Brandtner; Sarah Rieck; Michaela Matthey; Caroline Geisen; Benedikt Fels; Marta Stei; Kristina Kusche-Vihrog; Bernd K. Fleischmann; Daniela Wenzel (Angiogenesis, 2024)
Aortic aneurysm is characterized by a pathological dilation at specific predilection sites of the vessel and potentially results in life-threatening vascular rupture. Herein, we established a modified “Häutchen method” for the local isolation of endothelial cells (ECs) from mouse aorta to analyze their spatial heterogeneity and potential role in site-specific disease development. When we compared ECs from aneurysm predilection sites of healthy mice with adjacent control segments we found regulation of genes related to extracellular matrix remodeling, angiogenesis and inflammation, all pathways playing a critical role in aneurysm development. We also detected enhanced cortical stiffness of the endothelium at these sites. Gene expression of ECs from aneurysms of the AngII ApoE −/− model when compared to sham animals mimicked expression patterns from predilection sites of healthy animals. Thus, this work highlights a striking genetic and functional regional heterogeneity in aortic ECs of healthy mice, which defines the location of aortic aneurysm formation in disease.

ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature - Boryeong Pak; Minjung Kim; Orjin Han; Heon-Woo Lee; Alexandre Dubrac; Woosoung Choi; Jee Myung Yang; Kevin Boyé; Heewon Cho; Kathryn M. Citrin; Injune Kim; Anne Eichmann; et al. (Angiogenesis, 2024)

Botulinum neurotoxin serotype A inhibited ocular angiogenesis through modulating glial activation via SOCS3 - Austin T. Gregg; Tianxi Wang; Manon Szczepan; Enton Lam; Hitomi Yagi; Katherine Neilsen; Xingyan Wang; Lois E. H. Smith; Ye Sun (Angiogenesis, 2024)
Background Pathological angiogenesis causes significant vision loss in neovascular age-related macular degeneration and other retinopathies with neovascularization (NV). Neuronal/glial-vascular interactions influence the release of angiogenic and neurotrophic factors. We hypothesized that botulinum neurotoxin serotype A (BoNT/A) modulates pathological endothelial cell proliferation through glial cell activation and growth factor release. Methods A laser-induced choroidal NV (CNV) was employed to investigate the anti-angiogenic effects of BoNT/A. Fundus fluorescence angiography, immunohistochemistry, and real-time PCR were used to assess BoNT/A efficacy in inhibiting CNV and the molecular mechanisms underlying this inhibition. Neuronal and glial suppressor of cytokine signaling 3 (SOCS3) deficient mice were used to investigate the molecular mechanisms of BoNT/A in inhibiting CNV via SOCS3. Findings In laser-induced CNV mice with intravitreal BoNT/A treatment, CNV lesions decreased > 30%; vascular leakage and retinal glial activation were suppressed; and Socs3 mRNA expression was induced while vascular endothelial growth factor A ( Vegfa ) mRNA expression was suppressed. The protective effects of BoNT/A on CNV development were diminished in mice lacking neuronal/glial SOCS3. Conclusion BoNT/A suppressed laser-induced CNV and glial cell activation, in part through SOCS3 induction in neuronal/glial cells. BoNT/A treatment led to a decrease of pro-angiogenic factors, including VEGFA, highlighting the potential of BoNT/A as a therapeutic intervention for pathological angiogenesis in retinopathies.

A C-type lectin from Bothrops jararacussu venom reprograms endothelial cell biology - Federico G. Baudou; Nancy L. Charó; Marco A. Scheidegger; Juan C. Stupirski; Juan M. Pérez Sáez; María F. Troncoso; Mora Massaro; Adolfo R. de Roodt; Mauricio C. De Marzi; Mirta Schattner; Gabriel A. Rabinovich (Angiogenesis, 2024)

Lactate secreted by glycolytic conjunctival melanoma cells attracts and polarizes macrophages to drive angiogenesis in zebrafish xenografts - Jie Yin; Gabriel Forn-Cuní; Akshaya Mahalakshmi Surendran; Bruno Lopes-Bastos; Niki Pouliopoulou; Martine J. Jager; Sylvia E Le Dévédec; Quanchi Chen; B. Ewa Snaar-Jagalska (Angiogenesis, 2024)
Conjunctival melanoma (CoM) is a rare but potentially lethal cancer of the eye, with limited therapeutic option for metastases. A better understanding how primary CoM disseminate to form metastases is urgently needed in order to develop novel therapies. Previous studies indicated that primary CoM tumors express Vascular Endothelial Growth Factor (VEGF) and may recruit pro-tumorigenic M2-like macrophages. However, due to a lack of proper models, the expected role of angiogenesis in the metastatic dissemination of CoM is still unknown. We show that cells derived from two CoM cell lines induce a strong angiogenic response when xenografted in zebrafish larvae. CoM cells are highly glycolytic and secrete lactate, which recruits and polarizes human and zebrafish macrophages towards a M2-like phenotype. These macrophages elevate the levels of proangiogenic factors such as VEGF, TGF-β, and IL-10 in the tumor microenvironment to induce an angiogenic response towards the engrafted CoM cells in vivo. Chemical ablation of zebrafish macrophages or inhibition of glycolysis in CoM cells terminates this response, suggesting that attraction of lactate-dependent macrophages into engrafted CoM cells drives angiogenesis and serves as a possible dissemination mechanism for glycolytic CoM cells.

Breathing new life into tissue engineering: exploring cutting-edge vascularization strategies for skin substitutes - M. Zohaib Iqbal; Mahrukh Riaz; Thomas Biedermann; Agnes S. Klar (Angiogenesis, 2024)
Tissue-engineered skin substitutes (TESS) emerged as a new therapeutic option to improve skin transplantation. However, establishing an adequate and rapid vascularization in TESS is a critical factor for their clinical application and successful engraftment in patients. Therefore, several methods have been applied to improve the vascularization of skin substitutes including (i) modifying the structural and physicochemical properties of dermal scaffolds; (ii) activating biological scaffolds with growth factor-releasing systems or gene vectors; and (iii) developing prevascularized skin substitutes by loading scaffolds with capillary-forming cells. This review provides a detailed overview of the most recent and important developments in the vascularization strategies for skin substitutes. On the one hand, we present cell-based approaches using stem cells, microvascular fragments, adipose tissue derived stromal vascular fraction, endothelial cells derived from blood and skin as well as other pro-angiogenic stimulation methods. On the other hand, we discuss how distinct 3D bioprinting techniques and microfluidics, miRNA manipulation, cell sheet engineering and photosynthetic scaffolds like GelMA, can enhance skin vascularization for clinical applications. Finally, we summarize and discuss the challenges and prospects of the currently available vascularization techniques that may serve as a steppingstone to a mainstream application of skin tissue engineering. Graphical abstract

Differential endothelial cell cycle status in postnatal retinal vessels revealed using a novel PIP-FUCCI reporter and zonation analysis - Ziqing Liu; Natalie T. Tanke; Alexandra Neal; Tianji Yu; Tershona Branch; Arya Sharma; Jean G. Cook; Victoria L. Bautch (Angiogenesis, 2024)
Cell cycle regulation is critical to blood vessel formation and function, but how the endothelial cell cycle integrates with vascular regulation is not well-understood, and available dynamic cell cycle reporters do not precisely distinguish all cell cycle stage transitions in vivo. Here we characterized a recently developed improved cell cycle reporter (PIP-FUCCI) that precisely delineates S phase and the S/G2 transition. Live image analysis of primary endothelial cells revealed predicted temporal changes and well-defined stage transitions. A new inducible mouse cell cycle reporter allele was selectively expressed in postnatal retinal endothelial cells upon Cre-mediated activation and predicted endothelial cell cycle status. We developed a semi-automated zonation program to define endothelial cell cycle status in spatially defined and developmentally distinct retinal areas and found predicted cell cycle stage differences in arteries, veins, and remodeled and angiogenic capillaries. Surprisingly, the predicted dearth of S-phase proliferative tip cells relative to stalk cells at the vascular front was accompanied by an unexpected enrichment for endothelial tip and stalk cells in G2, suggesting G2 stalling as a contribution to tip-cell arrest and dynamics at the front. Thus, this improved reporter precisely defines endothelial cell cycle status in vivo and reveals novel G2 regulation that may contribute to unique aspects of blood vessel network expansion.

Correction: Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells - Bojana Lazovic; Hoang-Tuan Nguyen; Mohammadhassan Ansarizadeh; Leif Wigge; Franziska Kohl; Songyuan Li; Miguel Carracedo; Jere Kettunen; Luc Krimpenfort; Ramy Elgendy; Kati Richter; Laknee De Silva; et al. (Angiogenesis, 2024)

Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype - Timo Rademakers; Marco Manca; Han Jin; Tanguy Orban; Ljubica Matic Perisic; Hubertus J. M. Frissen; Frank Rühle; Petra Hautvast; Jos van Rijssel; Kim van Kuijk; Barend M. E. Mees; Carine J. Peutz-Kootstra; et al. (Angiogenesis, 2024)
The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 ( sptbn1 ) was identified as one of the central hubs of this module (along with zeb1 and dock1 ) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.

Generation and characterisation of scalable and stable human pluripotent stem cell-derived microvascular-like endothelial cells for cardiac applications - Qasim A. Majid; Bishwa R. Ghimire; Bela Merkely; Anna M. Randi; Sian E. Harding; Virpi Talman; Gábor Földes (Angiogenesis, 2024)
Coronary microvascular disease (CMD) and its progression towards major adverse coronary events pose a significant health challenge. Accurate in vitro investigation of CMD requires a robust cell model that faithfully represents the cells within the cardiac microvasculature. Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) offer great potential; however, they are traditionally derived via differentiation protocols that are not readily scalable and are not specified towards the microvasculature. Here, we report the development and comprehensive characterisation of a scalable 3D protocol enabling the generation of phenotypically stable cardiac hPSC-microvascular-like ECs (hPSC-CMVECs) and cardiac pericyte-like cells. These were derived by growing vascular organoids within 3D stirred tank bioreactors and subjecting the emerging 3D hPSC-ECs to high-concentration VEGF-A treatment (3DV). Not only did this promote phenotypic stability of the 3DV hPSC-ECs; single cell-RNA sequencing (scRNA-seq) revealed the pronounced expression of cardiac endothelial- and microvascular-associated genes. Further, the generated mural cells attained from the vascular organoid exhibited markers characteristic of cardiac pericytes. Thus, we present a suitable cell model for investigating the cardiac microvasculature as well as the endothelial-dependent and -independent mechanisms of CMD. Moreover, owing to their phenotypic stability, cardiac specificity, and high angiogenic potential, the cells described within would also be well suited for cardiac tissue engineering applications.

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells - Bojana Lazovic; Hoang-Tuan Nguyen; Mohammadhassan Ansarizadeh; Leif Wigge; Franziska Kohl; Songyuan Li; Miguel Carracedo; Jere Kettunen; Luc Krimpenfort; Ramy Elgendy; Kati Richter; Laknee De Silva; et al. (Angiogenesis, 2024)
Induced pluripotent stem cell (iPSC) derived endothelial cells (iECs) have emerged as a promising tool for studying vascular biology and providing a platform for modelling various vascular diseases, including those with genetic origins. Currently, primary ECs are the main source for disease modelling in this field. However, they are difficult to edit and have a limited lifespan. To study the effects of targeted mutations on an endogenous level, we generated and characterized an iPSC derived model for venous malformations (VMs). CRISPR-Cas9 technology was used to generate a novel human iPSC line with an amino acid substitution L914F in the TIE2 receptor, known to cause VMs. This enabled us to study the differential effects of VM causative mutations in iECs in multiple in vitro models and assess their ability to form vessels in vivo. The analysis of TIE2 expression levels in TIE2 L914F iECs showed a significantly lower expression of TIE2 on mRNA and protein level, which has not been observed before due to a lack of models with endogenous edited TIE2 L914F and sparse patient data. Interestingly, the TIE2 pathway was still significantly upregulated and TIE2 showed high levels of phosphorylation. TIE2 L914F iECs exhibited dysregulated angiogenesis markers and upregulated migration capability, while proliferation was not affected. Under shear stress TIE2 L914F iECs showed reduced alignment in the flow direction and a larger cell area than TIE2 WT iECs. In summary, we developed a novel TIE2 L914F iPSC-derived iEC model and characterized it in multiple in vitro models. The model can be used in future work for drug screening for novel treatments for VMs.

CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation - Ting-Ting Chang; Liang-Yu Lin; Ching Chen; Jaw-Wen Chen (Angiogenesis, 2024)
Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Distinct roles of SOX9 in self-renewal of progenitors and mesenchymal transition of the endothelium - Jilai Zhao; Laura Sormani; Sebastien Jacquelin; Haiming Li; Cassandra Styke; Chenhao Zhou; Jonathan Beesley; Linus Oon; Simranpreet Kaur; Seen-Ling Sim; Ho Yi Wong; James Dight; et al. (Angiogenesis, 2024)
Regenerative capabilities of the endothelium rely on vessel-resident progenitors termed endothelial colony forming cells (ECFCs). This study aimed to investigate if these progenitors are impacted by conditions (i.e., obesity or atherosclerosis) characterized by increased serum levels of oxidized low-density lipoprotein (oxLDL), a known inducer of Endothelial-to-Mesenchymal Transition (EndMT). Our investigation focused on understanding the effects of EndMT on the self-renewal capabilities of progenitors and the associated molecular alterations. In the presence of oxLDL, ECFCs displayed classical features of EndMT, through reduced endothelial gene and protein expression, function as well as increased mesenchymal genes, contractility, and motility. Additionally, ECFCs displayed a dramatic loss in self-renewal capacity in the presence of oxLDL. RNA-sequencing analysis of ECFCs exposed to oxLDL validated gene expression changes suggesting EndMT and identified SOX9 as one of the highly differentially expressed genes. ATAC sequencing analysis identified SOX9 binding sites associated with regions of dynamic chromosome accessibility resulting from oxLDL exposure, further pointing to its importance. EndMT phenotype and gene expression changes induced by oxLDL in vitro or high fat diet (HFD) in vivo were reversed by the silencing of SOX9 in ECFCs or the endothelial-specific conditional knockout of Sox9 in murine models. Overall, our findings support that EndMT affects vessel-resident endothelial progenitor’s self-renewal. SOX9 activation is an early transcriptional event that drives the mesenchymal transition of endothelial progenitor cells. The identification of the molecular network driving EndMT in vessel-resident endothelial progenitors presents a new avenue in understanding and preventing a range of condition where this process is involved.

Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity - Anthony R. Anzell; Amy B. Kunz; James P. Donovan; Thanhlong G. Tran; Xinyan Lu; Sarah Young; Beth L. Roman (Angiogenesis, 2024)

IC100, a humanized therapeutic monoclonal anti-ASC antibody alleviates oxygen-induced retinopathy in mice - Huijun Yuan; Shaoyi Chen; Matthew R. Duncan; Juan Pablo de Rivero Vaccari; Robert W. Keane; W. Dalton Dietrich; Tsung-Han Chou; Merline Benny; Augusto F. Schmidt; Karen Young; Kevin K. Park; Vittorio Porciatti; et al. (Angiogenesis, 2024)
Background Retinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation. Methods We first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O 2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O 2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O 2 with PBS (O 2 -PBS), O 2 + IC100 intravitreal injection (O 2 -IC100-IVT), and O 2 + IC100 intraperitoneal injection (O 2 -IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR. Results ASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O 2 . IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O 2 . Conclusion These data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP.

Systemic glucocorticoids use in post-COVID-syndrome patients does not affect retinal microcirculation - T. Kuchler; C. Schmaderer (Angiogenesis, 2024)

Correction: Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization - Gideon Obasanmi; Manjosh Uppal; Jing Z. Cui; Jeanne Xi; Myeong Jin Ju; Jun Song; Eleanor To; Siqi Li; Wania Khan; Darian Cheng; John Zhu; Lyden Irani; et al. (Angiogenesis, 2024)

Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations - Tianqi Tu; Jiaxing Yu; Chendan Jiang; Shikun Zhang; Jingwei Li; Jian Ren; Shiju Zhang; Yuan Zhou; Ziwei Cui; Haohan Lu; Xiaosheng Meng; Zhanjing Wang; et al. (Angiogenesis, 2024)

Systemic glucocorticoids link to long-term microvascular injury in COVID-19 - Qian Yang; Cai Yun Xia; Ying Cai; Yan Fang Zhang; Dao Ting Li; Shu Qi Wu; Peng Hu (Angiogenesis, 2024)

Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis - Carolin Christina Drost; Alexandros Rovas; Irina Osiaevi; Klaus Schughart; Alexander Lukasz; Wolfgang A. Linke; Hermann Pavenstädt; Philipp Kümpers (Angiogenesis, 2024)
Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (r s =0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (r s =-0.58, p p

Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism - Fan Yang; Gloria Lee; Yi Fan (Angiogenesis, 2024)
Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.

The role of vasculature and angiogenesis in respiratory diseases - Maximilian Ackermann; Christopher Werlein; Edith Plucinski; Sophie Leypold; Mark P. Kühnel; Stijn E. Verleden; Hassan A. Khalil; Florian Länger; Tobias Welte; Steven J. Mentzer; Danny D. Jonigk (Angiogenesis, 2024)
In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.

Microglia in retinal angiogenesis and diabetic retinopathy - Aiyan Hu; Mirko H. H. Schmidt; Nora Heinig (Angiogenesis, 2024)
Diabetic retinopathy has a high probability of causing visual impairment or blindness throughout the disease progression and is characterized by the growth of new blood vessels in the retina at an advanced, proliferative stage. Microglia are a resident immune population in the central nervous system, known to play a crucial role in regulating retinal angiogenesis in both physiological and pathological conditions, including diabetic retinopathy. Physiologically, they are located close to blood vessels and are essential for forming new blood vessels (neovascularization). In diabetic retinopathy, microglia become widely activated, showing a distinct polarization phenotype that leads to their accumulation around neovascular tufts. These activated microglia induce pathogenic angiogenesis through the secretion of various angiogenic factors and by regulating the status of endothelial cells. Interestingly, some subtypes of microglia simultaneously promote the regression of neovascularization tufts and normal angiogenesis in neovascularization lesions. Modulating the state of microglial activation to ameliorate neovascularization thus appears as a promising potential therapeutic approach for managing diabetic retinopathy. Graphical abstract

Vascular mimicry in zebrafish fin regeneration: how macrophages build new blood vessels - Anita Senk; Jennifer Fazzari; Valentin Djonov (Angiogenesis, 2024)
Vascular mimicry has been thoroughly investigated in tumor angiogenesis. In this study, we demonstrate for the first time that a process closely resembling tumor vascular mimicry is present during physiological blood vessel formation in tissue regeneration using the zebrafish fin regeneration assay. At the fin-regenerating front, vasculature is formed by mosaic blood vessels with endothelial-like cells possessing the morphological phenotype of a macrophage and co-expressing both endothelial and macrophage markers within single cells. Our data demonstrate that the vascular segments of the regenerating tissue expand, in part, through the transformation of adjacent macrophages into endothelial-like cells, forming functional, perfused channels and contributing to the de novo formation of microvasculature. Inhibiting the formation of tubular vascular-like structures by CVM-1118 prevents vascular mimicry and network formation resulting in a 70% shorter regeneration area with 60% reduced vessel growth and a complete absence of any signs of regeneration in half of the fin area. Additionally, this is associated with a significant reduction in macrophages. Furthermore, depleting macrophages using macrophage inhibitor PLX-3397, results in impaired tissue regeneration and blood vessel formation, namely a reduction in the regeneration area and vessel network by 75% in comparison to controls.

Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization - Gideon Obasanmi; Manjosh Uppal; Jing Z. Cui; Jeanne Xi; Myeong Jin Ju; Jun Song; Eleanor To; Siqi Li; Wania Khan; Darian Cheng; John Zhu; Lyden Irani; et al. (Angiogenesis, 2024)
Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD.

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos - Xudong Wang; Tianxi Wang; Satoshi Kaneko; Emil Kriukov; Enton Lam; Manon Szczepan; Jasmine Chen; Austin Gregg; Xingyan Wang; Angeles Fernandez-Gonzalez; S. Alex Mitsialis; Stella Kourembanas; et al. (Angiogenesis, 2024)
Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.

Connective tissue disorders in COVID-19: Reply to “People with a connective tissue disorder may be especially vulnerable to the endothelial damage that characterizes long COVID due to the fragility of their vasculature and slow wound healing” - Xiaoming Wu; Valerie A. Novakovic; Jialan Shi (Angiogenesis, 2024)

Group XIV C-type lectins: emerging targets in tumor angiogenesis - Elliott J. Yee; Isaac Vigil; Yi Sun; Robert J. Torphy; Richard D. Schulick; Yuwen Zhu (Angiogenesis, 2024)
C-type lectins, distinguished by a C-type lectin binding domain (CTLD), are an evolutionarily conserved superfamily of glycoproteins that are implicated in a broad range of physiologic processes. The group XIV subfamily of CTLDs are comprised of CD93, CD248/endosialin, CLEC14a, and thrombomodulin/CD141, and have important roles in creating and maintaining blood vessels, organizing extracellular matrix, and balancing pro- and anti-coagulative processes. As such, dysregulation in the expression and downstream signaling pathways of these proteins often lead to clinically relevant pathology. Recently, group XIV CTLDs have been shown to play significant roles in cancer progression, namely tumor angiogenesis and metastatic dissemination. Interest in therapeutically targeting tumor vasculature is increasing and the search for novel angiogenic targets is ongoing. Group XIV CTLDs have emerged as key moderators of tumor angiogenesis and metastasis, thus offering substantial therapeutic promise for the clinic. Herein, we review our current knowledge of group XIV CTLDs, discuss each’s role in malignancy and associated potential therapeutic avenues, briefly discuss group XIV CTLDs in the context of two other relevant lectin families, and offer future direction in further elucidating mechanisms by which these proteins function and facilitate tumor growth.

Vascularized organoid-on-a-chip: design, imaging, and analysis - Tingting Yu; Qihang Yang; Bo Peng; Zhongze Gu; Dan Zhu (Angiogenesis, 2024)

2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases - T. J. Zech; A. Wolf; M. Hector; I. Bischoff-Kont; G. M. Krishnathas; S. Kuntschar; T. Schmid; F. Bracher; T. Langmann; R. Fürst (Angiogenesis, 2024)
Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current anti-angiogenic treatments still have major drawbacks like limited efficacy in diseases that also rely on inflammation. Therefore, new anti-angiogenic approaches are sorely needed, and simultaneous inhibition of angiogenesis and inflammation is desirable. Here, we show that 2-desaza-annomontine (C81), a derivative of the plant alkaloid annomontine previously shown to inhibit endothelial inflammation, impedes angiogenesis by inhibiting CDC2-like kinases (CLKs) and WNT/ β -catenin signaling. C81 reduced choroidal neovascularization in a laser-induced murine in vivo model, inhibited sprouting from vascular endothelial growth factor A (VEGF-A)-activated murine aortic rings ex vivo, and reduced angiogenesis-related activities of endothelial cells in multiple functional assays. This was largely phenocopied by CLK inhibitors and knockdowns, but not by inhibitors of the other known targets of C81. Mechanistically, CLK inhibition reduced VEGF receptor 2 (VEGFR2) mRNA and protein expression as well as downstream signaling. This was partly caused by a reduction of WNT/ β -catenin pathway activity, as activating the pathway induced, while β -catenin knockdown impeded VEGFR2 expression. Surprisingly, alternative splicing of VEGFR2 was not detected. In summary, C81 and other CLK inhibitors could be promising compounds in the treatment of diseases that depend on angiogenesis and inflammation due to their impairment of both processes. Graphical abstract

Evidence of premature vascular dysfunction in young adults who regularly use e-cigarettes and the impact of usage length - Chloe Matheson; Tijana Simovic; Allison Heefner; Marisa Colon; Enrique Tunon; Kolton Cobb; Christopher Thode; Alison Breland; Caroline O. Cobb; Patrick Nana-Sinkam; Ryan Garten; Paula Rodriguez-Miguelez (Angiogenesis, 2024)
Background Electronic (e-) cigarettes are increasingly popular tobacco products on the US market. Traditional tobacco products are known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. However, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. Methods Twenty-one regular users of e-cigarettes (ECU) and twenty-one demographically matched non-users (NU) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality, endothelium-dependent vasodilation (EDD), and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). Results Our results suggest that regular users of e-cigarettes present with premature microvascular impairment when compared to non-users. Specifically, they exhibit lower hyperemic ( p = 0.003), thermal ( p = 0.010), and EDD ( p = 0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than 3 years also present with systemic manifestations, as observed by significantly reduced macrovascular ( p = 0.002) and microvascular ( p ≤ 0.044) function. Conclusions Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation when compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than 3 years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes.

A high-resolution view of the heterogeneous aging endothelium - Sarah Dobner; Fanni Tóth; Laura P. M. H. de Rooij (Angiogenesis, 2024)
Vascular endothelial cell (EC) aging has a strong impact on tissue perfusion and overall cardiovascular health. While studies confined to the investigation of aging-associated vascular readouts in one or a few tissues have already drastically expanded our understanding of EC aging, single-cell omics and other high-resolution profiling technologies have started to illuminate the intricate molecular changes underlying endothelial aging across diverse tissues and vascular beds at scale. In this review, we provide an overview of recent insights into the heterogeneous adaptations of the aging vascular endothelium. We address critical questions regarding tissue-specific and universal responses of the endothelium to the aging process, EC turnover dynamics throughout lifespan, and the differential susceptibility of ECs to acquiring aging-associated traits. In doing so, we underscore the transformative potential of single-cell approaches in advancing our comprehension of endothelial aging, essential to foster the development of future innovative therapeutic strategies for aging-associated vascular conditions.

People with a connective tissue disorder may be especially vulnerable to the endothelial damage that characterizes long COVID due to the fragility of their vasculature and slow wound healing - Jeffrey Lubell (Angiogenesis, 2024)

Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors - T. Al Tabosh; H. Liu; D. Koça; M. Al Tarrass; L. Tu; S. Giraud; L. Delagrange; M. Beaudoin; S. Rivière; V. Grobost; M. Rondeau-Lutz; O. Dupuis; et al. (Angiogenesis, 2024)
Heterozygous activin receptor-like kinase 1 ( ALK1 ) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1 -mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe ( LFNG ), was validated by RT-qPCR in three different ALK1 -mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

Role of endothelial PDGFB in arterio-venous malformations pathogenesis - Yanzhu Lin; Johannes Gahn; Kuheli Banerjee; Gergana Dobreva; Mahak Singhal; Alexandre Dubrac; Roxana Ola (Angiogenesis, 2024)
Arterial-venous malformations (AVMs) are direct connections between arteries and veins without an intervening capillary bed. Either familial inherited or sporadically occurring, localized pericytes (PCs) drop is among the AVMs’ hallmarks. Whether impaired PC coverage triggers AVMs or it is a secondary event is unclear. Here we evaluated the role of the master regulator of PC recruitment, Platelet derived growth factor B (PDGFB) in AVM pathogenesis. Using tamoxifen-inducible deletion of Pdgfb in endothelial cells (ECs), we show that disruption of EC Pdgfb -mediated PC recruitment and maintenance leads to capillary enlargement and organotypic AVM-like structures. These vascular lesions contain non-proliferative hyperplastic, hypertrophic and miss-oriented capillary ECs with an altered capillary EC fate identity. Mechanistically, we propose that PDGFB maintains capillary EC size and caliber to limit hemodynamic changes, thus restricting expression of Krüppel like factor 4 and activation of Bone morphogenic protein, Transforming growth factor β and NOTCH signaling in ECs. Furthermore, our study emphasizes that inducing or activating PDGFB signaling may be a viable therapeutic approach for treating vascular malformations.

Notch ligands are biomarkers of anti-TNF response in RA patients - Stephanie R. Zack; Anja Meyer; Brian Zanotti; Michael V. Volin; Sania Deen; Neha Satoeya; Nadera Sweiss; Myles J. Lewis; Costantino Pitzalis; Jan K. Kitajewski; Shiva Shahrara (Angiogenesis, 2024)

Circulating Von Willebrand factor: a consistent biomarker predicting in-hospital mortality across different waves of the COVID-19 pandemic - David M. Smadja; Anne-Sophie Jannot; Aurélien Philippe; Estelle Lu; Jeanne Rancic; Olivier Sanchez; Richard Chocron; Nicolas Gendron; Jean-Luc Diehl (Angiogenesis, 2024)

Multimodality imaging reveals angiogenic evolution in vivo during calvarial bone defect healing - Yunke Ren; Xinying Chu; Janaka Senarathna; Akanksha Bhargava; Warren L. Grayson; Arvind P. Pathak (Angiogenesis, 2024)

Correction: The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells - Andrei Turtoi; Denis Mottet; Nicolas Matheus; Bruno Dumont; Paul Peixoto; Vincent Hennequière; Christophe Deroanne; Alain Colige; Edwin De Pauw; Akeila Bellahcène; Vincent Castronovo (Angiogenesis, 2024)

Targeting the microenvironment in the treatment of arteriovenous malformations - Caroline T. Seebauer; Benedikt Wiens; Constantin A. Hintschich; Natascha Platz Batista da Silva; Katja Evert; Frank Haubner; Friedrich G. Kapp; Christina Wendl; Kathrin Renner; Christopher Bohr; Thomas Kühnel; Veronika Vielsmeier (Angiogenesis, 2024)
Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31 + endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects. Graphical abstract Mechanical stress increases VEGF expression in endothelial AVM cells, possibly causing the VEGF upregulation in the microenvironment of AVM cells. The resulting RAS/RAF/MEK/ERK signaling in leads to progression of fast-flow malformations. The monoclonal VEGF-A antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. Sporadically occurring slow-flow malformations (LMs, VMs) have mutations in TEK or PIK3CA . TEK encodes the endothelial receptor tyrosine kinase TIE2. Sporadic extracranial fast-flow malformations (AVMs) show mutations in KRAS, BRAF and MAP2K1 , which encodes the dual specificity mitogen-activated protein kinase MEK1. Combined targeting of the molecular causes of the disease could be key to achieve symptom control and reduce lesion growth. Orange: gain-of-function; Blue, circled with orange: enhanced signaling.

A defined clathrin-mediated trafficking pathway regulates sFLT1/VEGFR1 secretion from endothelial cells - Karina Kinghorn; Amy Gill; Allison Marvin; Renee Li; Kaitlyn Quigley; Simcha Singh; Michaelanthony T. Gore; Ferdinand le Noble; Feilim Mac Gabhann; Victoria L. Bautch (Angiogenesis, 2024)
FLT1/VEGFR1 negatively regulates VEGF-A signaling and is required for proper vessel morphogenesis during vascular development and vessel homeostasis. Although a soluble isoform, sFLT1, is often mis-regulated in disease and aging, how sFLT1 is trafficked and secreted from endothelial cells is not well understood. Here we define requirements for constitutive sFLT1 trafficking and secretion in endothelial cells from the Golgi to the plasma membrane, and we show that sFLT1 secretion requires clathrin at or near the Golgi. Perturbations that affect sFLT1 trafficking blunted endothelial cell secretion and promoted intracellular mis-localization in cells and zebrafish embryos. siRNA-mediated depletion of specific trafficking components revealed requirements for RAB27A, VAMP3, and STX3 for post-Golgi vesicle trafficking and sFLT1 secretion, while STX6, ARF1, and AP1 were required at the Golgi. Live-imaging of temporally controlled sFLT1 release from the endoplasmic reticulum showed clathrin-dependent sFLT1 trafficking at the Golgi into secretory vesicles that then trafficked to the plasma membrane. Depletion of STX6 altered vessel sprouting in 3D, suggesting that endothelial cell sFLT1 secretion influences proper vessel sprouting. Thus, specific trafficking components provide a secretory path from the Golgi to the plasma membrane for sFLT1 in endothelial cells that utilizes a specialized clathrin-dependent intermediate, suggesting novel therapeutic targets.

VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients - Aurélien Philippe; Sven Günther; Jeanne Rancic; Pauline Cavagna; Bertrand Renaud; Nicolas Gendron; Elie Mousseaux; Thông Hua-Huy; Guillaume Reverdito; Benjamin Planquette; Olivier Sanchez; Pascale Gaussem; et al. (Angiogenesis, 2024)

Phenotypic screening in Organ-on-a-Chip systems: a 1537 kinase inhibitor library screen on a 3D angiogenesis assay - Camilla Soragni; Karla Queiroz; Chee Ping Ng; Arthur Stok; Thomas Olivier; Dora Tzagkaraki; Jeroen Heijmans; Johnny Suijker; Sander P. M. de Ruiter; Aleksandra Olczyk; Marleen Bokkers; Frederik Schavemaker; et al. (Angiogenesis, 2024)
Modern drug development increasingly requires comprehensive models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screening exercise in a high-throughput Organ-on-a-Chip setup. We assessed the inhibitory effect of 1537 protein kinase inhibitors in an angiogenesis assay. Over 4000 micro-vessels were grown under perfusion flow in microfluidic chips, exposed to a cocktail of pro-angiogenic factors and subsequently exposed to the respective kinase inhibitors. Efficacy of compounds was evaluated by reduced angiogenic sprouting, whereas reduced integrity of the main micro-vessel was taken as a measure for toxicity. The screen yielded 53 hits with high anti-angiogenicity and low toxicity, of which 44 were previously unassociated with angiogenic pathways. This study demonstrates that Organ-on-a-Chip models can be screened in high numbers to identify novel compounds and targets. This will ultimately reduce bias in early-stage drug development and increases probability to identify first in class compounds and targets for today’s intractable diseases.

Capillary rarefaction: a missing link in renal and cardiovascular disease? - Floor M. E. G. Steegh; Anke A. Keijbeck; Patrick A. de Hoogt; Timo Rademakers; Alfons J. H. M. Houben; Koen D. Reesink; Coen D. A. Stehouwer; Mat J. A. P. Daemen; Carine J. Peutz-Kootstra (Angiogenesis, 2024)

Damage to endothelial barriers and its contribution to long COVID - Xiaoming Wu; Mengqi Xiang; Haijiao Jing; Chengyue Wang; Valerie A. Novakovic; Jialan Shi (Angiogenesis, 2024)

Reply to “Embracing imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19” - Xiaoming Wu; Jialan Shi (Angiogenesis, 2023)

The modes of angiogenesis: an updated perspective - Andrew C. Dudley; Arjan W. Griffioen (Angiogenesis, 2023)

Correction: Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation - Timon Kuchler; Roman Günthner; Andrea Ribeiro; Renate Hausinger; Lukas Streese; Anna Wöhnl; Veronika Kesseler; Johanna Negele; Tarek Assali; Javier Carbajo-Lozoya; Maciej Lech; Heike Schneider; et al. (Angiogenesis, 2023)

Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice - Shota Shimizu; Tomohiro Iba; Hisamichi Naito; Fitriana Nur Rahmawati; Hirotaka Konishi; Weizhen Jia; Fumitaka Muramatsu; Nobuyuki Takakura (Angiogenesis, 2023)
Tissue-resident vascular endothelial stem cells (VESCs), marked by expression of CD157, possess long-term repopulating potential and contribute to vascular regeneration and homeostasis in mice. Stem cell exhaustion is regarded as one of the hallmarks of aging and is being extensively studied in several types of tissue-resident stem cells; however, how aging affects VESCs has not been clarified yet. In the present study, we isolated VESCs from young and aged mice to compare their potential to differentiate into endothelial cells in vitro and in vivo. Here, we report that the number of liver endothelial cells (ECs) including VESCs was lower in aged (27–28 month-old) than young (2–3 month-old) mice. In vitro culture of primary VESCs revealed that the potential to generate ECs is impaired in aged VESCs isolated from liver and lung relative to young VESCs. Orthotopic transplantation of VESCs showed that aged VESCs and their progeny expand less efficiently than their young counterparts when transplanted into aged mice, but they are equally functional in young recipients. Gene expression analysis indicated that inflammatory signaling was more activated in aged ECs including VESCs. Using single-cell RNA sequencing data from the Tabula Muris Consortium, we show that T cells and monocyte/macrophage lineage cells including Kupffer cells are enriched in the aged liver. These immune cells produce IL-1β and several chemokines, suggesting the possible involvement of age-associated inflammation in the functional decline of VESCs with age.

Embracing Imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19 - Chia Siang Kow; Dinesh Sangarran Ramachandram; Syed Shahzad Hasan (Angiogenesis, 2023)

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation - Timon Kuchler; Roman Günthner; Andrea Ribeiro; Renate Hausinger; Lukas Streese; Anna Wöhnl; Veronika Kesseler; Johanna Negele; Tarek Assali; Javier Carbajo-Lozoya; Maciej Lech; Heike Schneider; et al. (Angiogenesis, 2023)
Background Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. Methods In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort ( n = 41, matched out of n = 204). Measurements and main results PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR ( R = − 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. Conclusion Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. Trial registration This study was previously registered at ClinicalTrials (“All Eyes on PCS—Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552 ). Graphical abstract Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com

FOXO1 promotes endothelial cell elongation and angiogenesis by up-regulating the phosphorylation of myosin light chain 2 - Kiyomi Tsuji-Tamura; Minetaro Ogawa (Angiogenesis, 2023)

Correction to: BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways - Hao Zhou; Chen Shi; Shunying Hu; Hong Zhu; Jun Ren; Yundai Chen (Angiogenesis, 2023)

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia - Lea Scherschinski; Chul Han; Yong Hwan Kim; Ethan A. Winkler; Joshua S. Catapano; Tyler D. Schriber; Peter Vajkoczy; Michael T. Lawton; S. Paul Oh (Angiogenesis, 2023)
Background Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. Methods Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26 CreER ; Alk1 2f/2f ( Alk1 -iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. Results Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1 -iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3−9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. Conclusions We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model’s longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

The dynamics of the endothelial glycocalyx: a rare snapshot by electron microscopy - Carolin C. Drost; Andreas Unger; Wolfgang A. Linke; Hans Vink; Philipp Kümpers (Angiogenesis, 2023)

Effect of erythrophagocytosis-induced ferroptosis during angiogenesis in atherosclerotic plaques - Pauline Puylaert; Lynn Roth; Melissa Van Praet; Isabel Pintelon; Catalina Dumitrascu; Alexander van Nuijs; Greta Klejborowska; Pieter-Jan Guns; Tom Vanden Berghe; Koen Augustyns; Guido R. Y. De Meyer; Wim Martinet (Angiogenesis, 2023)
Intraplaque (IP) angiogenesis is a key feature of advanced atherosclerotic plaques. Because IP vessels are fragile and leaky, erythrocytes are released and phagocytosed by macrophages (erythrophagocytosis), which leads to high intracellular iron content, lipid peroxidation and cell death. In vitro experiments showed that erythrophagocytosis by macrophages induced non-canonical ferroptosis, an emerging type of regulated necrosis that may contribute to plaque destabilization. Erythrophagocytosis-induced ferroptosis was accompanied by increased expression of heme-oxygenase 1 and ferritin, and could be blocked by co-treatment with third generation ferroptosis inhibitor UAMC-3203. Both heme-oxygenase 1 and ferritin were also expressed in erythrocyte-rich regions of carotid plaques from ApoE −/− Fbn1 C1039G+/− mice, a model of advanced atherosclerosis with IP angiogenesis. The effect of UAMC-3203 (12.35 mg/kg/day) on atherosclerosis was evaluated in ApoE −/− Fbn1 C1039G+/− mice fed a western-type diet (WD) for 12 weeks (n = 13 mice/group) or 20 weeks (n = 16–21 mice/group) to distinguish between plaques without and with established IP angiogenesis, respectively. A significant decrease in carotid plaque thickness was observed after 20 weeks WD (87 ± 19 μm vs. 166 ± 20 μm, p = 0.006), particularly in plaques with confirmed IP angiogenesis or hemorrhage (108 ± 35 μm vs. 322 ± 40 μm, p = 0.004). This effect was accompanied by decreased IP heme-oxygenase 1 and ferritin expression. UAMC-3203 did not affect carotid plaques after 12 weeks WD or plaques in the aorta, which typically do not develop IP angiogenesis. Altogether, erythrophagocytosis-induced ferroptosis during IP angiogenesis leads to larger atherosclerotic plaques, an effect that can be prevented by ferroptosis inhibitor UAMC-3203.