Executive summary of the 14th HHT international scientific conference - Roxana Ola; Josefien Hessels; Adrienne Hammill; Cassi Friday; Marianne Clancy; Hanny Al-Samkari; Stryder Meadows; Vivek Iyer; Rosemary Akhurst (Angiogenesis, 2023)
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin- ENG , activin like kinase 1 ACVRL1 aka ALK1, and SMAD4 ) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000. Expert clinicians and international scientists gathered in Cascais, Portugal from September 29th to October 2 nd , 2022 to present the latest scientific research in the HHT field and novel treatment strategies for people living with HHT. During the largest HHT scientific conference yet, participants included 293 in person and 46 virtually. An impressive 209 abstracts were accepted to the meeting and 59 were selected for oral presentations. The remaining 150 abstracts were presented during judged poster sessions. This review article summarizes the basic and clinical abstracts selected as oral presentations with their new observations and discoveries as well as surrounding discussion and debate. Two discussion-based workshops were also held during the conference, each focusing on mechanisms and clinical perspectives in either AVM formation and progression or current and future therapies for HHT. Our hope is that this paper will represent the current progress and the remaining unanswered questions surrounding HHT, in order to serve as an update for those within the field and an invitation to those scientists and clinicians as yet outside of the field of HHT.

2022 14th HHT International Scientific Conference Abstracts (Angiogenesis, 2023)

Correction: Nectins and Nectin-like molecules drive vascular development and barrier function - Doryssa Hermans; Carla Rodriguez-Mogeda; Hannelore Kemps; Annelies Bronckaers; Helga E. de Vries; Bieke Broux (Angiogenesis, 2023)

Pathological angiogenesis: mechanisms and therapeutic strategies - Andrew C. Dudley; Arjan W. Griffioen (Angiogenesis, 2023)
In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

Expansion and collapse of VEGF diversity in major clades of the animal kingdom - Khushbu Rauniyar; Honey Bokharaie; Michael Jeltsch (Angiogenesis, 2023)
Together with the platelet-derived growth factors (PDGFs), the vascular endothelial growth factors (VEGFs) form the PDGF/VEGF subgroup among cystine knot growth factors. The evolutionary relationships within this subgroup have not been examined thoroughly to date. Here, we comprehensively analyze the PDGF/VEGF growth factors throughout all animal phyla and propose a phylogenetic tree. Vertebrate whole-genome duplications play a role in expanding PDGF/VEGF diversity, but several limited duplications are necessary to account for the temporal pattern of emergence. The phylogenetically oldest PDGF/VEGF-like growth factor likely featured a C-terminus with a BR3P signature, a hallmark of the modern-day lymphangiogenic growth factors VEGF-C and VEGF-D. Some younger VEGF genes, such as VEGFB and PGF , appeared completely absent in important vertebrate clades such as birds and amphibia, respectively. In contrast, individual PDGF/VEGF gene duplications frequently occurred in fish on top of the known fish-specific whole-genome duplications. The lack of precise counterparts for human genes poses limitations but also offers opportunities for research using organisms that diverge considerably from humans. Graphical abstract Sources for the graphical abstract: 326 MYA and older [1]; 72–240 MYA [2]; 235–65 MYA [3]

Diminished vasculogenesis under inflammatory conditions is mediated by Activin A - Sahana Manohar-Sindhu; Stephanie Merfeld-Clauss; Yana Goddard; Keith L. March; Dmitry O. Traktuev (Angiogenesis, 2023)

Design and preclinical evaluation of a novel apelin-based PET radiotracer targeting APJ receptor for molecular imaging of angiogenesis - Béatrice Louis; Vincent Nail; Oriane Nachar; Ahlem Bouhlel; Anaïs Moyon; Laure Balasse; Stéphanie Simoncini; Adrien Chabert; Samantha Fernandez; Pauline Brige; Guillaume Hache; Aura Tintaru; et al. (Angiogenesis, 2023)
APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([ 68 Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [ 67 Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [ 68 Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [ 68 Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [ 68 Ga]Ga-AP747 and [ 68 Ga]Ga-RGD 2 small animal PET/CT. [ 68 Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [ 68 Ga]Ga-RGD 2 . Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [ 68 Ga]Ga-AP747 PET signal was more than twice higher than that of [ 68 Ga]Ga-RGD 2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [ 68 Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [ 68 Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [ 68 Ga]Ga-RGD 2 .

FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP - Zhongjie Fu; Pia Lundgren; Aldina Pivodic; Hitomi Yagi; Jarrod C. Harman; Jay Yang; Minji Ko; Katherine Neilsen; Saswata Talukdar; Ann Hellström; Lois E. H. Smith (Angiogenesis, 2023)
Hyperglycemia in early postnatal life of preterm infants with incompletely vascularized retinas is associated with increased risk of potentially blinding neovascular retinopathy of prematurity (ROP). Neovascular ROP (Phase II ROP) is a compensatory but ultimately pathological response to the suppression of physiological postnatal retinal vascular development (Phase I ROP). Hyperglycemia in neonatal mice which suppresses physiological retinal vascular growth is associated with decreased expression of systemic and retinal fibroblast growth factor 21 (FGF21). FGF21 administration promoted and FGF21 deficiency suppressed the physiological retinal vessel growth. FGF21 increased serum adiponectin (APN) levels and loss of APN abolished FGF21 promotion of physiological retinal vascular development. Blocking mitochondrial fatty acid oxidation also abolished FGF21 protection against delayed physiological retinal vessel growth. Clinically, preterm infants developing severe neovascular ROP (versus non-severe ROP) had a lower total lipid intake with more parenteral and less enteral during the first 4 weeks of life. Our data suggest that increasing FGF21 levels in the presence of adequate enteral lipids may help prevent Phase I retinopathy (and therefore prevent neovascular disease).

The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions - Zheng Fan; Raphaela Ardicoglu; Aashil A. Batavia; Ruslan Rust; Lukas von Ziegler; Rebecca Waag; Jing Zhang; Thibaut Desgeorges; Oliver Sturman; Hairuo Dang; Rebecca Weber; Martin Roszkowski; et al. (Angiogenesis, 2023)
The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1 −/− mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1 −/− mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1 and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

Nectins and Nectin-like molecules drive vascular development and barrier function - Doryssa Hermans; Carla Rodriguez-Mogeda; Hannelore Kemps; Annelies Bronckaers; Helga E. de Vries; Bieke Broux (Angiogenesis, 2023)

Endothelial cells require functional FLVCR1a during developmental and adult angiogenesis - Sara Petrillo; F. De Giorgio; F. Bertino; F. Garello; V. Bitonto; D. L. Longo; S. Mercurio; G. Ammirata; A. L. Allocco; V. Fiorito; D. Chiabrando; F. Altruda; et al. (Angiogenesis, 2023)
The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a transmembrane heme exporter essential for embryonic vascular development. However, the exact role of FLVCR1a during blood vessel development remains largely undefined. Here, we show that FLVCR1a is highly expressed in angiogenic endothelial cells (ECs) compared to quiescent ECs. Consistently, ECs lacking FLVCR1a give rise to structurally and functionally abnormal vascular networks in multiple models of developmental and pathologic angiogenesis. Firstly, zebrafish embryos without FLVCR1a displayed defective intersegmental vessels formation. Furthermore, endothelial-specific Flvcr1a targeting in mice led to a reduced radial expansion of the retinal vasculature associated to decreased EC proliferation. Moreover, Flvcr1a null retinas showed defective vascular organization and loose attachment of pericytes. Finally, adult neo-angiogenesis is severely affected in murine models of tumor angiogenesis. Tumor blood vessels lacking Flvcr1a were disorganized and dysfunctional. Collectively, our results demonstrate the critical role of FLVCR1a as a regulator of developmental and pathological angiogenesis identifying FLVCR1a as a potential therapeutic target in human diseases characterized by aberrant neovascularization.

Modeling angiogenesis in the human brain in a tissue-engineered post-capillary venule - Nan Zhao; Sarah Kulkarni; Sophia Zhang; Raleigh M. Linville; Tracy D. Chung; Zhaobin Guo; John J. Jamieson; Danielle Norman; Lily Liang; Alexander F. Pessell; Peter Searson (Angiogenesis, 2023)

Loss of GLTSCR1 causes congenital heart defects by regulating NPPA transcription - Fengyan Han; Beibei Yang; Yan Chen; Lu Liu; Xiaoqing Cheng; Jiaqi Huang; Ke Zhou; Dandan Zhang; Enping Xu; Maode Lai; Bingjian Lv; Hongqiang Cheng; et al. (Angiogenesis, 2023)
Precise and specific spatiotemporal domains of gene expression regulation are critical for embryonic development. Recent studies have identified GLTSCR1 as a gene transcriptional elongation regulator in cancer research. However, the function of GLTSCR1, especially in embryonic development, remains poorly understood. Here, we found that GLTSCR1 was essential for cardiac development because Gltscr1 knockout (Gltscr1 −/− ) led to embryonic lethality in mice with severe congenital heart defects (CHDs). Ventricular septal defect and double outflow right ventricular were also observed in neural crest cells with conditional deletion of Gltscr1, which were associated with neonatal lethality in mice. Mechanistically, GLTSCR1 deletion promoted NPPA expression by coordinating the CHD risk G allele of rs56153133 in the NPPA enhancer and releasing the transcription factor ZNF740-binding site on the NPPA promoter. These findings demonstrated that GLTSCR1 acts as a candidate CHD-related gene.

Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation - Ran Huo; Yingxi Yang; Yingfan Sun; Qiuxia Zhou; Shaozhi Zhao; Zongchao Mo; Hongyuan Xu; Jie Wang; Jiancong Weng; Yuming Jiao; Junze Zhang; Qiheng He; et al. (Angiogenesis, 2023)

Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy - Patrycja Nowak-Sliwinska; Judy R. van Beijnum; Christian J. Griffioen; Zowi R. Huinen; Nadine Grima Sopesens; Ralph Schulz; Samir V. Jenkins; Ruud P. M. Dings; Floris H. Groenendijk; Elisabeth J. M. Huijbers; Victor L. J. L. Thijssen; Eric Jonasch; et al. (Angiogenesis, 2023)
Purpose Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions. Experimental design Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration. Results It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment. Conclusion The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds.

Endothelial Rap1B mediates T-cell exclusion to promote tumor growth: a novel mechanism underlying vascular immunosuppression - Guru Prasad Sharma; Ramoji Kosuru; Sribalaji Lakshmikanthan; Shikan Zheng; Yao Chen; Robert Burns; Gang Xin; Weiguo Cui; Magdalena Chrzanowska (Angiogenesis, 2023)

Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties - Timothy Sargis; Seock-Won Youn; Krishna Thakkar; L. A. Naiche; Na Yoon Paik; Kostandin V. Pajcini; Jan K. Kitajewski (Angiogenesis, 2023)
The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10–14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10–14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition.

Inflammation and vascular remodeling in COVID-19 hearts - Christopher Werlein; Maximilian Ackermann; Helge Stark; Harshit R. Shah; Alexandar Tzankov; Jasmin Dinonne Haslbauer; Saskia von Stillfried; Roman David Bülow; Ali El-Armouche; Stephan Kuenzel; Jan Lukas Robertus; Marius Reichardt; et al. (Angiogenesis, 2023)
A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A ( n = 16), lymphocytic non-influenza myocarditis cases ( n = 8), and non-inflamed heart tissue ( n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + —macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

Retraction Note: Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma - Xiang-Guang Wu; Chen-Fei Zhou; Yan-Mei Zhang; Rui-Ming Yan; Wen-Fei Wei; Xiao-Jing Chen; Hong-Yan Yi; Luo-Jiao Liang; Liang-sheng Fan; Li Liang; Sha Wu; Wei Wang (Angiogenesis, 2023)

BMP10 functions independently from BMP9 for the development of a proper arteriovenous network - Hyunwoo Choi; Bo-Gyeong Kim; Yong Hwan Kim; Se-Jin Lee; Young Jae Lee; S. Paul Oh (Angiogenesis, 2023)
Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-β (TGF-β) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10 -inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9 -KO, and Bmp9/10 -double KO (dKO) mice. Bmp10 -iKO and Bmp9/10 -dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9 -KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10 -iKO and Bmp9/10 -dKO mice was detected. Bmp9/10 -dKO mice exhibited the lethality and vascular malformation similar to Bmp10 -iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10 -dKO and endothelial-specific Eng -iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression - Beatriz G. S. Rocha; Caroline C. Picoli; Bryan O. P. Gonçalves; Walison N. Silva; Alinne C. Costa; Michele M. Moraes; Pedro A. C. Costa; Gabryella S. P. Santos; Milla R. Almeida; Luciana M. Silva; Youvika Singh; Marcelo Falchetti; et al. (Angiogenesis, 2023)

Correction: RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway - Kailiang Qiao; Yantao Liu; Zheng Xu; Haohao Zhang; Heng Zhang; Chao Zhang; Zhi Chang; Xinyan Lu; Zhongwei Li; Ce Luo; Yanrong Liu; Cheng Yang; et al. (Angiogenesis, 2023)

Correction: A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner - Xiao-Jing Chen; Wen-Fei Wei; Zi-Ci Wang; Nisha Wang; Chu-Hong Guo; Chen-Fei Zhou; Luo-Jiao Liang; Sha Wu; Li Liang; Wei Wang (Angiogenesis, 2023)

Correction: Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats - Jin-Hang Gao; Shi-Lei Wen; Shi Feng; Wen-Juan Yang; Yao-Yao Lu; Huan Tong; Rui Liu; Shi-Hang Tang; Zhi-Yin Huang; Ying-Mei Tang; Jin-Hui Yang; Hui-Qi Xie; et al. (Angiogenesis, 2023)

MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia - Michael G. McCoy; Anurag Jamaiyar; Grasiele Sausen; Henry S. Cheng; Daniel Pérez-Cremades; Rulin Zhuang; Jingshu Chen; Philip P. Goodney; Mark A. Creager; Marc S. Sabatine; Marc P. Bonaca; Mark W. Feinberg (Angiogenesis, 2023)

Protein disulfide isomerase A1 as a novel redox sensor in VEGFR2 signaling and angiogenesis - Sheela Nagarkoti; Young-Mee Kim; Dipankar Ash; Archita Das; Eric Vitriol; Tracy-Ann Read; Seock-Won Youn; Varadarajan Sudhahar; Malgorzata McMenamin; Yali Hou; Harriet Boatwright; Ruth Caldwell; et al. (Angiogenesis, 2023)

Endothelial cell expression of mutant Map2k1 causes vascular malformations in mice - Patrick J. Smits; Christopher L. Sudduth; Dennis J. Konczyk; Yu Sheng Cheng; Matthew P. Vivero; Harry P. W. Kozakewich; Matthew L. Warman; Arin K. Greene (Angiogenesis, 2023)

Persistent capillary rarefication in long COVID syndrome - Irina Osiaevi; Arik Schulze; Georg Evers; Kimon Harmening; Hans Vink; Philipp Kümpers; Michael Mohr; Alexandros Rovas (Angiogenesis, 2023)
Background Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection. Methods This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients ( n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4–25 µm. Measurements and main results Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: − 45.16%; D6: − 35.60%; D7: − 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002). Conclusions Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

Tissue oxygenation stabilizes neovessels and mitigates hemorrhages in human atherosclerosis-induced angiogenesis - Alfred C. Aplin; Roberto F. Nicosia (Angiogenesis, 2023)

Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations - Hiroki Hongo; Satoru Miyawaki; Yu Teranishi; Jun Mitsui; Hiroto Katoh; Daisuke Komura; Kinya Tsubota; Takashi Matsukawa; Masakatsu Watanabe; Masakazu Kurita; Jun Yoshimura; Shogo Dofuku; et al. (Angiogenesis, 2023)
Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4 , which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

S100A4-dependent glycolysis promotes lymphatic vessel sprouting in tumor - Anqi Li; Linyu Zhu; Ningjing Lei; Jiajia Wan; Xixi Duan; Shuangqing Liu; Yanru Cheng; Ming Wang; Zhuoyu Gu; Huilei Zhang; Yueyue Bai; Li Zhang; et al. (Angiogenesis, 2023)

Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer - Yi Zhang; Lei Zhou; Yixin Xu; Jingyu Zhou; Tao Jiang; Jiaqi Wang; Chao Li; Xiaoxiong Sun; Hu Song; Jun Song (Angiogenesis, 2023)

The rising impact of angiogenesis research - Arjan W. Griffioen; Andrew C. Dudley (Angiogenesis, 2022)

PDGFD switches on stem cell endothelial commitment - Weisi Lu; Peipei Xu; Boxiong Deng; Jianing Zhang; Ying Zhan; Xianchai Lin; Xiangzhong Xu; Zhaoxia Xia; Xiaoxi Yang; Xiaoling Zeng; Lijuan Huang; Bingbing Xie; et al. (Angiogenesis, 2022)
The critical factors regulating stem cell endothelial commitment and renewal remain not well understood. Here, using loss- and gain-of-function assays together with bioinformatic analysis and multiple model systems, we show that PDGFD is an essential factor that switches on endothelial commitment of embryonic stem cells (ESCs). PDGFD genetic deletion or knockdown inhibits ESC differentiation into EC lineage and increases ESC self-renewal, and PDGFD overexpression activates ESC differentiation towards ECs. RNA sequencing reveals a critical requirement of PDGFD for the expression of vascular-differentiation related genes in ESCs. Importantly, PDGFD genetic deletion or knockdown increases ESC self-renewal and decreases blood vessel densities in both embryonic and neonatal mice and in teratomas. Mechanistically, we reveal that PDGFD fulfills this function via the MAPK/ERK pathway. Our findings provide new insight of PDGFD as a novel regulator of ESC fate determination, and suggest therapeutic implications of modulating PDGFD activity in stem cell therapy.

Angiogenesis in adipose tissue and obesity - Silvia Corvera; Javier Solivan-Rivera; Zinger Yang Loureiro (Angiogenesis, 2022)
While most tissues exhibit their greatest growth during development, adipose tissue is capable of additional massive expansion in adults. Adipose tissue expandability is advantageous when temporarily storing fuel for use during fasting, but becomes pathological upon continuous food intake, leading to obesity and its many comorbidities. The dense vasculature of adipose tissue provides necessary oxygen and nutrients, and supports delivery of fuel to and from adipocytes under fed or fasting conditions. Moreover, the vasculature of adipose tissue comprises a major niche for multipotent progenitor cells, which give rise to new adipocytes and are necessary for tissue repair. Given the multiple, pivotal roles of the adipose tissue vasculature, impairments in angiogenic capacity may underlie obesity-associated diseases such as diabetes and cardiometabolic disease. Exciting new studies on the single-cell and single-nuclei composition of adipose tissues in mouse and humans are providing new insights into mechanisms of adipose tissue angiogenesis. Moreover, new modes of intercellular communication involving micro vesicle and exosome transfer of proteins, nucleic acids and organelles are also being recognized to play key roles. This review focuses on new insights on the cellular and signaling mechanisms underlying adipose tissue angiogenesis, and on their impact on obesity and its pathophysiological consequences.

Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial - Yuuki Shimizu; Kazuhisa Kondo; Ryo Hayashida; Ken-ichiro Sasaki; Masanori Ohtsuka; Yoshihiro Fukumoto; Shinichiro Takashima; Oto Inoue; Soichiro Usui; Masayuki Takamura; Masashi Sakuma; Teruo Inoue; et al. (Angiogenesis, 2022)

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study - Alexandros Rovas; Konrad Buscher; Irina Osiaevi; Carolin Christina Drost; Jan Sackarnd; Phil-Robin Tepasse; Manfred Fobker; Joachim Kühn; Stephan Braune; Ulrich Göbel; Gerold Thölking; Andreas Gröschel; et al. (Angiogenesis, 2022)
Aims Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. Methods and results This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p Conclusion Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes. Graphical abstract

In vitro grafting of hepatic spheroids and organoids on a microfluidic vascular bed - Flavio Bonanini; Dorota Kurek; Sara Previdi; Arnaud Nicolas; Delilah Hendriks; Sander de Ruiter; Marine Meyer; Maria Clapés Cabrer; Roelof Dinkelberg; Silvia Bonilla García; Bart Kramer; Thomas Olivier; et al. (Angiogenesis, 2022)
With recent progress in modeling liver organogenesis and regeneration, the lack of vasculature is becoming the bottleneck in progressing our ability to model human hepatic tissues in vitro. Here, we introduce a platform for routine grafting of liver and other tissues on an in vitro grown microvascular bed. The platform consists of 64 microfluidic chips patterned underneath a 384-well microtiter plate. Each chip allows the formation of a microvascular bed between two main lateral vessels by inducing angiogenesis. Chips consist of an open-top microfluidic chamber, which enables addition of a target tissue by manual or robotic pipetting. Upon grafting a liver microtissue, the microvascular bed undergoes anastomosis, resulting in a stable, perfusable vascular network. Interactions with vasculature were found in spheroids and organoids upon 7 days of co-culture with space of Disse-like architecture in between hepatocytes and endothelium. Veno-occlusive disease was induced by azathioprine exposure, leading to impeded perfusion of the vascularized spheroid. The platform holds the potential to replace animals with an in vitro alternative for routine grafting of spheroids, organoids, or (patient-derived) explants.

A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis - F. Galeffi; D. A. Snellings; S. E. Wetzel-Strong; N. Kastelic; J. Bullock; C. J. Gallione; P. E. North; D. A. Marchuk (Angiogenesis, 2022)

TFEB controls integrin-mediated endothelial cell adhesion by the regulation of cholesterol metabolism - Camilla Ariano; Chiara Riganti; Davide Corà; Donatella Valdembri; Giulia Mana; Elena Astanina; Guido Serini; Federico Bussolino; Gabriella Doronzo (Angiogenesis, 2022)
The dynamic integrin-mediated adhesion of endothelial cells (ECs) to the surrounding ECM is fundamental for angiogenesis both in physiological and pathological conditions, such as embryonic development and cancer progression. The dynamics of EC-to-ECM adhesions relies on the regulation of the conformational activation and trafficking of integrins. Here, we reveal that oncogenic transcription factor EB (TFEB), a known regulator of lysosomal biogenesis and metabolism, also controls a transcriptional program that influences the turnover of ECM adhesions in ECs by regulating cholesterol metabolism. We show that TFEB favors ECM adhesion turnover by promoting the transcription of genes that drive the synthesis of cholesterol, which promotes the aggregation of caveolin-1, and the caveolin-dependent endocytosis of integrin β1. These findings suggest that TFEB might represent a novel target for the pharmacological control of pathological angiogenesis and bring new insights in the mechanism sustaining TFEB control of endocytosis.

Trafficking in blood vessel development - Caitlin R. Francis; Erich J. Kushner (Angiogenesis, 2022)
Blood vessels demonstrate a multitude of complex signaling programs that work in concert to produce functional vasculature networks during development. A known, but less widely studied, area of endothelial cell regulation is vesicular trafficking, also termed sorting. After moving through the Golgi apparatus, proteins are shuttled to organelles, plugged into membranes, recycled, or degraded depending on the internal and extrinsic cues. A snapshot of these protein-sorting systems can be viewed as a trafficking signature that is not only unique to endothelial tissue, but critically important for blood vessel form and function. In this review, we will cover how vesicular trafficking impacts various aspects of angiogenesis, such as sprouting, lumen formation, vessel stabilization, and secretion, emphasizing the role of Rab GTPase family members and their various effectors.

KIT is dispensable for physiological organ vascularisation in the embryo - Carlotta Tacconi; Alice Plein; Chiara Colletto; Emanuela Villa; Laura Denti; Cristiana Barone; Yousef Javanmardi; Emad Moeendarbary; Emanuele Azzoni; Alessandro Fantin; Christiana Ruhrberg (Angiogenesis, 2022)
Blood vessels form vast networks in all vertebrate organs to sustain tissue growth, repair and homeostatic metabolism, but they also contribute to a range of diseases with neovascularisation. It is, therefore, important to define the molecular mechanisms that underpin blood vessel growth. The receptor tyrosine kinase KIT is required for the normal expansion of hematopoietic progenitors that arise during embryogenesis from hemogenic endothelium in the yolk sac and dorsal aorta. Additionally, KIT has been reported to be expressed in endothelial cells during embryonic brain vascularisation and has been implicated in pathological angiogenesis. However, it is neither known whether KIT expression is widespread in normal organ endothelium nor whether it promotes blood vessel growth in developing organs. Here, we have used single-cell analyses to show that KIT is expressed in endothelial cell subsets of several organs, both in the adult and in the developing embryo. Knockout mouse analyses revealed that KIT is dispensable for vascularisation of growing organs in the midgestation embryo, including the lung, liver and brain. By contrast, vascular changes emerged during late-stage embryogenesis in these organs from KIT-deficient embryos, concurrent with severe erythrocyte deficiency and growth retardation. These findings suggest that KIT is not required for developmental tissue vascularisation in physiological conditions, but that KIT deficiency causes foetal anaemia at late gestation and thereby pathological vascular remodelling.

NRASQ61R mutation in human endothelial cells causes vascular malformations - Elisa Boscolo; Patricia Pastura; Sandra Schrenk; Jillian Goines; Rachael Kang; Devin Pillis; Punam Malik; Timothy D. Le Cras (Angiogenesis, 2022)

In vivo dissection of Rhoa function in vascular development using zebrafish - Laura M. Pillay; Joseph J. Yano; Andrew E. Davis; Matthew G. Butler; Megan O. Ezeude; Jong S. Park; Keith A. Barnes; Vanessa L. Reyes; Daniel Castranova; Aniket V. Gore; Matthew R. Swift; James R. Iben; et al. (Angiogenesis, 2022)

Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance - Danan Sun; Jin Wang; Sam Toan; David Muid; Ruibing Li; Xing Chang; Hao Zhou (Angiogenesis, 2022)

Capillary morphogenesis gene 2 (CMG2) mediates growth factor-induced angiogenesis by regulating endothelial cell chemotaxis - Lorna M. Cryan; Tsz-Ming Tsang; Jessica Stiles; Lauren Bazinet; Sai Lun Lee; Samuel Garrard; Erika Madrian; Cody Roberts; Jessie Payne; Andrew Jensen; Arthur E. Frankel; P. Christine Ackroyd; et al. (Angiogenesis, 2022)

The vascularization paradox of non-union formation - Maximilian M. Menger; Matthias W. Laschke; Andreas K. Nussler; Michael D. Menger; Tina Histing (Angiogenesis, 2022)
Despite major research efforts to elucidate mechanisms of non-union formation, failed fracture healing remains a common complication in orthopedic surgery. Adequate vascularization has been recognized as a crucial factor for successful bone regeneration, as newly formed microvessels guarantee the supply of the callus tissue with vital oxygen, nutrients, and growth factors. Accordingly, a vast number of preclinical studies have focused on the development of vascularization strategies to stimulate fracture repair. However, recent evidence suggests that stimulation of blood vessel formation is an oversimplified approach to support bone regeneration. This review discusses the role of vascularization during bone regeneration and delineates a phenomenon, for which we coin the term “the vascularization paradox of non-union-formation”. This view is based on the results of a variety of experimental studies that suggest that the callus tissue of non-unions is indeed densely vascularized and that pro-angiogenic mediators, such as vascular endothelial growth factor, are sufficiently expressed at the facture site. By gaining further insights into the molecular and cellular basis of non-union vascularization, it may be possible to develop more optimized treatment approaches or even prevent the non-union formation in the future.

Identification of vascular cues contributing to cancer cell stemness and function - Saran Kumar; Libat Bar-Lev; Husni Sharife; Myriam Grunewald; Maxim Mogilevsky; Tamar Licht; Jermaine Goveia; Federico Taverna; Iddo Paldor; Peter Carmeliet; Eli Keshet (Angiogenesis, 2022)

Angiopoietin-2-induced lymphatic endothelial cell migration drives lymphangiogenesis via the β1 integrin-RhoA-formin axis - Racheal Grace Akwii; Md. Sanaullah Sajib; Fatema Tuz Zahra; Paul Tullar; Masoud Zabet-Moghaddam; Yi Zheng; J. Silvio Gutkind; Colleen L. Doci; Constantinos M. Mikelis (Angiogenesis, 2022)

Plasma ratio of angiopoietin-2 to angiopoietin-1 is a biomarker of vascular impairment in chronic obstructive pulmonary disease patients - Fares Gouzi; Aurélien Philippe; Léo Blervaque; Sven Günther; Anne Virsolvy; Maxime Gruest; Olivier Cazorla; Elisa Rossi; David M. Smadja (Angiogenesis, 2022)

Deletion of endothelial α-parvin inhibits tumour angiogenesis, reduces tumour growth and induces tumour cell apoptosis - Yara Onetti; Roland E. Kälin; Bettina Pitter; Mengzhuo Hou; Victor Arribas; Rainer Glass; Eloi Montanez (Angiogenesis, 2022)

Copper stress impairs angiogenesis and lymphangiogenesis during zebrafish embryogenesis by down-regulating pERK1/2-foxm1-MMP2/9 axis and epigenetically regulating ccbe1 expression - Zhipeng Tai; Lingya Li; Guang Zhao; Jing-Xia Liu (Angiogenesis, 2022)

PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis - Harri Elamaa; Mika Kaakinen; Marjut Nätynki; Zoltan Szabo; Veli-Pekka Ronkainen; Ville Äijälä; Joni M. Mäki; Risto Kerkelä; Johanna Myllyharju; Lauri Eklund (Angiogenesis, 2022)
Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however, the pathophysiological relevance of PHD2 in the major arterial cell types; endothelial cells (ECs) and arterial smooth muscle cells (aSMCs) in the adult vasculature is incompletely characterized. Here, we investigated PHD2-dependent vascular homeostasis utilizing inducible deletions of PHD2 either in ECs ( Phd2 ∆ECi ) or in aSMCs ( Phd2 ∆aSMC ). Cardiovascular function and lung pathologies were studied using echocardiography, Doppler ultrasonography, intraventricular pressure measurement, histological, ultrastructural, and transcriptional methods. Cell intrinsic responses were investigated in hypoxia and in conditions mimicking hypertension-induced hemodynamic stress. Phd2 ∆ECi resulted in progressive pulmonary disease characterized by a thickened respiratory basement membrane (BM), alveolar fibrosis, increased pulmonary artery pressure, and adaptive hypertrophy of the right ventricle (RV). A low oxygen environment resulted in alterations in cultured ECs similar to those in Phd2 ∆ECi mice, involving BM components and vascular tone regulators favoring the contraction of SMCs. In contrast, Phd2 ∆aSMC resulted in elevated RV pressure without alterations in vascular tone regulators. Mechanistically, PHD2 inhibition in aSMCs involved actin polymerization -related tension development via activated cofilin. The results also indicated that hemodynamic stress, rather than PHD2-dependent hypoxia response alone, potentiates structural remodeling of the extracellular matrix in the pulmonary microvasculature and respiratory failure.

Interferon-alpha or -beta facilitates SARS-CoV-2 pulmonary vascular infection by inducing ACE2 - Timothy Klouda; Yuan Hao; Hyunbum Kim; Jiwon Kim; Judith Olejnik; Adam J. Hume; Sowntharya Ayyappan; Xuechong Hong; Juan Melero-Martin; Yinshan Fang; Qiong Wang; Xiaobo Zhou; et al. (Angiogenesis, 2022)
Severe viral pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a hyperinflammatory state typified by elevated circulating pro-inflammatory cytokines, frequently leading to potentially lethal vascular complications including thromboembolism, disseminated intracellular coagulopathy and vasculitis. Though endothelial infection and subsequent endothelial damage have been described in patients with fatal COVID-19, the mechanism by which this occurs remains elusive, particularly given that, under naïve conditions, pulmonary endothelial cells demonstrate minimal cell surface expression of the SARS-CoV-2 binding receptor ACE2. Herein we describe SARS-CoV-2 infection of the pulmonary endothelium in postmortem lung samples from individuals who died of COVID-19, demonstrating both heterogeneous ACE2 expression and endothelial damage. In primary endothelial cell cultures, we show that SARS-CoV-2 infection is dependent on the induction of ACE2 protein expression and that this process is facilitated by type 1 interferon-alpha (IFNα) or -beta(β)—two of the main anti-viral cytokines induced in severe SARS-CoV-2 infection—but not significantly by other cytokines (including interleukin 6 and interferon γ/λ). Our findings suggest that the stereotypical anti-viral interferon response may paradoxically facilitate the propagation of COVID-19 from the respiratory epithelium to the vasculature, raising concerns regarding the use of exogenous IFNα/β in the treatment of patients with COVID-19.

Unique functions for Notch4 in murine embryonic lymphangiogenesis - Ajit Muley; Minji Kim Uh; Glicella Salazar-De Simone; Bhairavi Swaminathan; Jennifer M. James; Aino Murtomaki; Seock Won Youn; Joseph D. McCarron; Chris Kitajewski; Maria Gnarra Buethe; Gloria Riitano; Yoh-suke Mukouyama; et al. (Angiogenesis, 2022)
In mice, embryonic dermal lymphatic development is well understood and used to study gene functions in lymphangiogenesis. Notch signaling is an evolutionarily conserved pathway that modulates cell fate decisions, which has been shown to both inhibit and promote dermal lymphangiogenesis. Here, we demonstrate distinct roles for Notch4 signaling versus canonical Notch signaling in embryonic dermal lymphangiogenesis. Actively growing embryonic dermal lymphatics expressed NOTCH1, NOTCH4, and DLL4 which correlated with Notch activity. In lymphatic endothelial cells (LECs), DLL4 activation of Notch induced a subset of Notch effectors and lymphatic genes, which were distinctly regulated by Notch1 and Notch4 activation. Treatment of LECs with VEGF-A or VEGF-C upregulated Dll4 transcripts and differentially and temporally regulated the expression of Notch1 and Hes / Hey genes. Mice nullizygous for Notch4 had an increase in the closure of the lymphangiogenic fronts which correlated with reduced vessel caliber in the maturing lymphatic plexus at E14.5 and reduced branching at E16.5. Activation of Notch4 suppressed LEC migration in a wounding assay significantly more than Notch1, suggesting a dominant role for Notch4 in regulating LEC migration. Unlike Notch4 nulls, inhibition of canonical Notch signaling by expressing a dominant negative form of MAML1 (DNMAML) in Prox1+ LECs led to increased lymphatic density consistent with an increase in LEC proliferation, described for the loss of LEC Notch1 . Moreover, loss of Notch4 did not affect LEC canonical Notch signaling. Thus, we propose that Notch4 signaling and canonical Notch signaling have distinct functions in the coordination of embryonic dermal lymphangiogenesis.

Blood vessels sense dermal stiffness via a novel mechanotransducer, APJ - Mika Sawane; Yuki Ogura; Ayano Nakamura; Hitomi Otaka; Hiroyasu Kidoya; Katsujiro Sato; Nobuyuki Takakura; Kentaro Kajiya (Angiogenesis, 2022)

Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma - Ngar Woon Kam; Ka Chun Wu; Wei Dai; Ying Wang; Leo Yik Chun Yan; Reshma Shakya; Rajiv Khanna; Yanru Qin; Simon Law; Anthony Wing Ip Lo; Victor Ho Fun Lee; Xin-Yuan Guan; et al. (Angiogenesis, 2022)
Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.

Opposite response of lung adenocarcinoma and its choroidal metastases upon ramucirumab plus docetaxel therapy after immunotherapy: a case report - Kinnosuke Matsumoto; Takayuki Shiroyama; Noriyasu Hashida; Kotaro Miyake; Yuji Yamamoto; Tomoki Kuge; Midori Yoneda; Makoto Yamamoto; Yujiro Naito; Yasuhiko Suga; Kiyoharu Fukushima; Shohei Koyama; et al. (Angiogenesis, 2022)

Chemerin regulates normal angiogenesis and hypoxia-driven neovascularization - Cyrine Ben Dhaou; Kamel Mandi; Mickaël Frye; Angela Acheampong; Ayoub Radi; Benjamin De Becker; Mathieu Antoine; Nicolas Baeyens; Valérie Wittamer; Marc Parmentier (Angiogenesis, 2022)
Chemerin is a multifunctional protein initially characterized in our laboratory as a chemoattractant factor for leukocyte populations. Its main functional receptor is CMKLR1. We identified previously chemerin as an anti-tumoral factor inhibiting the vascularization of tumor grafts. We show here that overexpression of bioactive chemerin in mice results in a reduction of the density of the retinal vascular network during its development and in adults. Chemerin did not affect vascular sprouting during the post-natal development of the network, but rather promoted endothelial cell apoptosis and vessel pruning. This phenotype was reversed to normal in CMKLR1-deficient mice, demonstrating the role of this receptor. Chemerin inhibited also neoangiogenesis in a model of pathological proliferative retinopathy, and in response to hind-limb ischemia. Mechanistically, PTEN and FOXO1 antagonists could almost completely restore the density of the retinal vasculature, suggesting the involvement of the PI3-kinase/AKT pathway in the chemerin-induced vessel regression process.

On coalescent angiogenesis and the remarkable flexibility of blood vessels - Francesco Pezzella; Robert S. Kerbel (Angiogenesis, 2022)

Coalescent angiogenesis—evidence for a novel concept of vascular network maturation - Bianca Nitzsche; Wen Wei Rong; Andrean Goede; Björn Hoffmann; Fabio Scarpa; Wolfgang M. Kuebler; Timothy W. Secomb; Axel R. Pries (Angiogenesis, 2022)
Angiogenesis describes the formation of new blood vessels from pre-existing vascular structures. While the most studied mode of angiogenesis is vascular sprouting, specific conditions or organs favor intussusception, i.e., the division or splitting of an existing vessel, as preferential mode of new vessel formation. In the present study, sustained (33-h) intravital microscopy of the vasculature in the chick chorioallantoic membrane (CAM) led to the hypothesis of a novel non-sprouting mode for vessel generation, which we termed “coalescent angiogenesis.” In this process, preferential flow pathways evolve from isotropic capillary meshes enclosing tissue islands. These preferential flow pathways progressively enlarge by coalescence of capillaries and elimination of internal tissue pillars, in a process that is the reverse of intussusception. Concomitantly, less perfused segments regress. In this way, an initially mesh-like capillary network is remodeled into a tree structure, while conserving vascular wall components and maintaining blood flow. Coalescent angiogenesis, thus, describes the remodeling of an initial, hemodynamically inefficient mesh structure, into a hierarchical tree structure that provides efficient convective transport, allowing for the rapid expansion of the vasculature with maintained blood supply and function during development.

Resident vascular endothelial progenitor definition and function: the age of reckoning - James Dight; Jilai Zhao; Cassandra Styke; Kiarash Khosrotehrani; Jatin Patel (Angiogenesis, 2022)
The cardiovascular system is composed around the central function of the endothelium that lines the inner surfaces of its vessels. In recent years, the existence of a progenitor population within the endothelium has been validated through the study of endothelial colony-forming cells (ECFCs) in human peripheral blood and certain vascular beds. However, our knowledge on endothelial populations in vivo that can give rise to ECFCs in culture has been limited. In this review we report and analyse recent attempts at describing progenitor populations in vivo from murine studies that reflect the self-renewal and stemness capacity observed in ECFCs. We pinpoint seminal discoveries within the field, which have phenotypically defined, and functionally scrutinised these endothelial progenitors. Furthermore, we review recent publications utilising single-cell sequencing technologies to better understand the endothelium in homeostasis and pathology.

Role of TGFβ1 and WNT6 in FGF2 and BMP4-driven endothelial differentiation of murine embryonic stem cells - Anna Gualandris; Alessio Noghero; Davide Cora’; Elena Astanina; Marco Arese; Federico Bussolino (Angiogenesis, 2022)
Embryonic stem cells (ES) are a valuable source of endothelial cells. By co-culturing ES cells with the stromal PA6 cells, the endothelial commitment can be achieved by adding exogenous FGF2 or BMP4. In this work, the molecular pathways that direct the differentiation of ES cells toward endothelium in response to FGF2 are evaluated and compared to those activated by BMP4. To this purpose the genes expression profiles of both ES/PA6 co-cultures and of pure cultures of PA6 cells were obtained by microarray technique at different time points. The bioinformatics processing of the data indicated TGFβ1 as the most represented upstream regulator in FGF2-induced endothelial commitment while WNT pathway as the most represented in BMP4-activated endothelial differentiation. Loss of function experiments were performed to validate the importance of TGFβ1 and WNT6 respectively in FGF2 and BMP4-induced endothelial differentiation. The loss of TGFβ1 expression significantly impaired the accomplishment of the endothelial commitment unless exogenous recombinant TGFβ1 was added to the culture medium. Similarly, silencing WNT6 expression partially affected the endothelial differentiation of the ES cells upon BMP4 stimulation. Such dysfunction was recovered by the addition of recombinant WNT6 to the culture medium. The ES/PA6 co-culture system recreates an in vitro complete microenvironment in which endothelial commitment is accomplished in response to alternative signals through different mechanisms. Given the importance of WNT and TGFβ1 in mediating the crosstalk between tumor and stromal cells this work adds new insights in the mechanism of tumor angiogenesis and of its possible inhibition.

PFKFB3 gene deletion in endothelial cells inhibits intraplaque angiogenesis and lesion formation in a murine model of venous bypass grafting - Paola Perrotta; Margreet R. de Vries; Bart Peeters; Pieter-Jan Guns; Guido R. Y. De Meyer; Paul H. A. Quax; Wim Martinet (Angiogenesis, 2022)
Vein grafting is a frequently used surgical intervention for cardiac revascularization. However, vein grafts display regions with intraplaque (IP) angiogenesis, which promotes atherogenesis and formation of unstable plaques. Graft neovessels are mainly composed of endothelial cells (ECs) that largely depend on glycolysis for migration and proliferation. In the present study, we aimed to investigate whether loss of the glycolytic flux enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) in ECs inhibits IP angiogenesis and as such prevents unstable plaque formation. To this end, apolipoprotein E deficient (ApoE −/− ) mice were backcrossed to a previously generated PFKFB3 fl/fl Cdh5 iCre mouse strain. Animals were injected with either corn oil (ApoE −/− PFKFB3 fl/fl ) or tamoxifen (ApoE −/− PFKFB3 ECKO ), and were fed a western-type diet for 4 weeks prior to vein grafting. Hereafter, mice received a western diet for an additional 28 days and were then sacrificed for graft assessment. Size and thickness of vein graft lesions decreased by 35 and 32%, respectively, in ApoE −/− PFKFB3 ECKO mice compared to controls, while stenosis diminished by 23%. Moreover, vein graft lesions in ApoE −/− PFKFB3 ECKO mice showed a significant reduction in macrophage infiltration (29%), number of neovessels (62%), and hemorrhages (86%). EC-specific PFKFB3 deletion did not show obvious adverse effects or changes in general metabolism. Interestingly, RT-PCR showed an increased M2 macrophage signature in vein grafts from ApoE −/− PFKFB3 ECKO mice. Altogether, EC-specific PFKFB3 gene deletion leads to a significant reduction in lesion size, IP angiogenesis, and hemorrhagic complications in vein grafts. This study demonstrates that inhibition of endothelial glycolysis is a promising therapeutic strategy to slow down plaque progression.

Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis - Yaxing Li; Longmei Zhao; Hui Zhang; Huiqi Xie (Angiogenesis, 2022)

Refractory systemic capillary leak syndrome treated with bevacizumab: a case report - Pin Wang; Chien-Hui Chan; Hsuan-Fei Chen; Woei-Yau Kao; Tzu-Rong Peng (Angiogenesis, 2022)

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling - Kondababu Kurakula; Quint A. J. Hagdorn; Diederik E. van der Feen; Anton Vonk Noordegraaf; Peter ten Dijke; Rudolf A. de Boer; Harm Jan Bogaard; Marie José Goumans; Rolf M. F. Berger (Angiogenesis, 2022)
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

Correction to: Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation - Joana Amado-Azevedo; Anne-Marieke D. van Stalborch; Erik T. Valent; Kalim Nawaz; Jan van Bezu; Etto C. Eringa; Femke P. M. Hoevenaars; Iris M. De Cuyper; Peter L. Hordijk; Victor W. M. van Hinsbergh; Geerten P. van Nieuw Amerongen; Jurjan Aman; et al. (Angiogenesis, 2022)

Successful management of lung adenocarcinoma with ALK/EGFR co-alterations and PD-L1 over-expression by bevacizumab combined with chemotherapy - Hengqiu He; Wendi Yang; Yusheng Huang; Xiaoyue Zhang; Yuan Peng; Zhenzhou Yang (Angiogenesis, 2022)

Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia - Joseph G. Parambil; James R. Gossage; Keith R. McCrae; Troy D. Woodard; K. V. Narayanan Menon; Kasi L. Timmerman; Douglas P. Pederson; Dennis L. Sprecher; Hanny Al-Samkari (Angiogenesis, 2022)

Extracellular matrix stiffness controls VEGF165 secretion and neuroblastoma angiogenesis via the YAP/RUNX2/SRSF1 axis - Min Bao; Yi Chen; Ji-Ting Liu; Han Bao; Wen-Bin Wang; Ying-Xin Qi; Fan Lv (Angiogenesis, 2022)

The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide - Juan Pablo Robles; Magdalena Zamora; Lourdes Siqueiros-Marquez; Elva Adan-Castro; Gabriela Ramirez-Hernandez; Francisco Freinet Nuñez; Fernando Lopez-Casillas; Robert P. Millar; Thomas Bertsch; Gonzalo Martínez de la Escalera; Jakob Triebel; Carmen Clapp (Angiogenesis, 2022)
The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.

Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance) - Julia C. F. Quintanilha; Yingmiao Liu; Amy S. Etheridge; Akram Yazdani; Hedy L. Kindler; William Kevin Kelly; Andrew B. Nixon; Federico Innocenti (Angiogenesis, 2022)

CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype - Daphné Raphaëlle Vannier; Apeksha Shapeti; Florent Chuffart; Emmanuelle Planus; Sandra Manet; Paul Rivier; Olivier Destaing; Corinne Albiges-Rizo; Hans Van Oosterwyck; Eva Faurobert (Angiogenesis, 2021)

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects - David M. Smadja; Steven J. Mentzer; Michaela Fontenay; Mike A. Laffan; Maximilian Ackermann; Julie Helms; Danny Jonigk; Richard Chocron; Gerald B. Pier; Nicolas Gendron; Stephanie Pons; Jean-Luc Diehl; et al. (Angiogenesis, 2021)

Von Willebrand factor multimers during non-invasive ultrasound therapy for aortic valve stenosis - David M. Smadja; Guillaume Goudot; Nicolas Gendron; Samuel Zarka; Etienne Puymirat; Aurélien Philippe; Christian Spaulding; Christophe Peronino; Mickael Tanter; Mathieu Pernot; Emmanuel Messas (Angiogenesis, 2021)

Correction to: Notch regulates vascular collagen IV basement membrane through modulation of lysyl hydroxylase 3 trafficking - Stephen J. Gross; Amelia M. Webb; Alek D. Peterlin; Jessica R. Durrant; Rachel J. Judson; Qanber Raza; Jan K. Kitajewski; Erich J. Kushner (Angiogenesis, 2021)
A correction to this paper has been published: https://doi.org/10.1007/s10456-021-09801-w

Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome - Chih-Chieh Tsao; Julia Baumann; Sheng-Fu Huang; Diana Kindler; Aileen Schroeter; Nicole Kachappilly; Max Gassmann; Markus Rudin; Omolara O. Ogunshola (Angiogenesis, 2021)
Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying mechanisms remain unknown. Hypoxia-inducible factor-1 (HIF-1), a master regulator of injury responses, has divergent roles in different cells especially during stress scenarios. On one hand HIF-1 is neuroprotective but on the other it induces vascular permeability. Since pericytes are critical for barrier stability, we asked if pericyte HIF-1 signaling impacts barrier integrity and injury severity in a mouse model of ischemic stroke. We show that pericyte HIF-1 loss of function (LoF) diminishes ischemic damage and barrier permeability at 3 days reperfusion. HIF-1 deficiency preserved barrier integrity by reducing pericyte death thereby maintaining vessel coverage and junctional protein organization, and suppressing vascular remodeling. Importantly, considerable improvements in sensorimotor function were observed in HIF-1 LoF mice indicating that better vascular functionality post stroke improves outcome. Thus, boosting vascular integrity by inhibiting pericytic HIF-1 activation and/or increasing pericyte survival may be a lucrative option to accelerate recovery after severe brain injury.

Characterization of the heterogeneity of endothelial cells in bleomycin-induced lung fibrosis using single-cell RNA sequencing - Xiucheng Liu; Xichun Qin; Hao Qin; Caili Jia; Yanliang Yuan; Teng Sun; Bi Chen; Chang Chen; Hao Zhang (Angiogenesis, 2021)
The loss of normal alveolar capillary and deregulated angiogenesis occurs simultaneously in idiopathic pulmonary fibrosis (IPF); however the contributions of specific endothelial subpopulations in the development of pulmonary fibrosis are poorly understood. Herein, we perform single-cell RNA sequencing to characterize the heterogeneity of endothelial cells (ECs) in bleomycin (BLM)-induced lung fibrosis in rats. One subpopulation, characterized by the expression of Nos3 and Cav1, is mostly distributed in non-fibrotic lungs and also highly expresses genes related to the “response to mechanical stimulus” and “lung/heart morphogenesis” processes. Another subpopulation of ECs expanded in BLM-treated lungs, characterized by Cxcl12, is observed to be closely related to the pro-fibrotic process in the transcriptome data, such as “regulation of angiogenesis,” “collagen binding,” and “chemokine activity,” and spatially localized to BLM-induced neovascularization. Using CellPhoneDB software, we generated a complex cell–cell interaction network, which predicts the potential roles of EC subpopulations in recruiting monocytes, inducing the proliferation of fibroblasts and promoting the production and remolding of the extracellular matrix (ECM). Taken together, our data demonstrate the high degree of heterogeneity of ECs in fibrotic lung and it is proposed that the interaction between ECs, macrophages, and stromal cells contributes to pathologic IPF.

High endothelial venules (HEVs) in immunity, inflammation and cancer - Lucas Blanchard; Jean-Philippe Girard (Angiogenesis, 2021)
High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body’s own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn’s disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79 + tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3 + T cell-rich areas or CD20 + B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.

Notch regulates vascular collagen IV basement membrane through modulation of lysyl hydroxylase 3 trafficking - Stephen J. Gross; Amelia M. Webb; Alek D. Peterlin; Jessica R. Durrant; Rachel J. Judson; Qanber Raza; Jan K. Kitajewski; Erich J. Kushner (Angiogenesis, 2021)
Collagen type IV (Col IV) is a basement membrane protein associated with early blood vessel morphogenesis and is essential for blood vessel stability. Defects in vascular Col IV deposition are the basis of heritable disorders, such as small vessel disease, marked by cerebral hemorrhage and drastically shorten lifespan. To date, little is known about how endothelial cells regulate the intracellular transport and selective secretion of Col IV in response to angiogenic cues, leaving a void in our understanding of this critical process. Our aim was to identify trafficking pathways that regulate Col IV deposition during angiogenic blood vessel development. We have identified the GTPase Rab10 as a major regulator of Col IV vesicular trafficking during vascular development using both in vitro imaging and biochemistry as well as in vivo models. Knockdown of Rab10 reduced de novo Col IV secretion in vivo and in vitro. Mechanistically, we determined that Rab10 is an indirect mediator of Col IV secretion, partnering with atypical Rab25 to deliver the enzyme lysyl hydroxylase 3 (LH3) to Col IV-containing vesicles staged for secretion. Loss of Rab10 or Rab25 results in depletion of LH3 from Col IV-containing vesicles and rapid lysosomal degradation of Col IV. Furthermore, we demonstrate that Rab10 is Notch responsive, indicating a novel connection between permissive Notch-based vessel maturation programs and vesicle trafficking. Our results illustrate both a new trafficking-based component in the regulated secretion of Col IV and how this vesicle trafficking program interfaces with Notch signaling to fine-tune basement membrane secretion during blood vessel development.

Correction to: The role of redox system in metastasis formation - Chiara Cencioni; Valentina Comunanza; Emanuele Middonti; Edoardo Vallariello; Federico Bussolino (Angiogenesis, 2021)

Correction to: Phosphorylation of pericyte FAK‑Y861 affects tumour cell apoptosis and tumour blood vessel regression - Delphine M. Lees; Louise E. Reynolds; Ana Rita Pedrosa; Marina Roy-Luzarraga; Kairbaan M. Hodivala-Dilke (Angiogenesis, 2021)
A correction to this paper has been published: https://doi.org/10.1007/s10456-021-09802-9

Letter in response to: circulating von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality - P. Bhogal; G. Paul; G. Collins; O. Jaffer (Angiogenesis, 2021)

The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during angiogenesis - Lanette Kempers; Yuki Wakayama; Ivo van der Bijl; Charita Furumaya; Iris M. De Cuyper; Aldo Jongejan; Marije Kat; Anne-Marieke D. van Stalborch; Antonius L. van Boxtel; Marvin Hubert; Dirk Geerts; Jaap D. van Buul; et al. (Angiogenesis, 2021)
Sprouting angiogenesis is key to many pathophysiological conditions, and is strongly regulated by vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we report that the early endosomal GTPase Rab5C and its activator RIN2 prevent lysosomal routing and degradation of VEGF-bound, internalized VEGFR2 in human endothelial cells. Stabilization of endosomal VEGFR2 levels by RIN2/Rab5C is crucial for VEGF signaling through the ERK and PI3-K pathways, the expression of immediate VEGF target genes, as well as specification of angiogenic ‘tip’ and ‘stalk’ cell phenotypes and cell sprouting. Using overexpression of Rab mutants, knockdown and CRISPR/Cas9-mediated gene editing, and live-cell imaging in zebrafish, we further show that endosomal stabilization of VEGFR2 levels is required for developmental angiogenesis in vivo. In contrast, the premature degradation of internalized VEGFR2 disrupts VEGF signaling, gene expression, and tip cell formation and migration. Thus, an endosomal feedforward mechanism maintains receptor signaling by preventing lysosomal degradation, which is directly linked to the induction of target genes and cell fate in collectively migrating cells during morphogenesis.

Von Willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance - Aurélien Philippe; Nicolas Gendron; Olivier Bory; Agathe Beauvais; Tristan Mirault; Benjamin Planquette; Olivier Sanchez; Jean-Luc Diehl; Richard Chocron; David M. Smadja (Angiogenesis, 2021)

TAK1 signaling is a potential therapeutic target for pathological angiogenesis - Linxin Zhu; Suraj Lama; Leilei Tu; Gregory J. Dusting; Jiang-Hui Wang; Guei-Sheung Liu (Angiogenesis, 2021)

The role of redox system in metastasis formation - Chiara Cencioni; Valentina Comunanza; Emanuele Middonti; Edoardo Vallariello; Federico Bussolino (Angiogenesis, 2021)
The metastatic cancer disease represents the real and urgent clinical need in oncology. Therefore, an understanding of the complex molecular mechanisms sustaining the metastatic cascade is critical to advance cancer therapies. Recent studies highlight how redox signaling influences the behavior of metastatic cancer cells, contributes to their travel in bloodstream from the primary tumor to the distant organs and conditions the progression of the micrometastases or their dormant state. Radical oxygen species not only regulate intracellular processes but participate to paracrine circuits by diffusion to nearby cells, thus assuming unpredicted roles in the communication between metastatic cancer cells, blood circulating cells, and stroma cells at site of colonization. Here, we review recent insights in the role of radical oxygen species in the metastasis formation with a special focus on extravasation at metastatic sites.

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation - Joana Amado-Azevedo; Anne-Marieke D. van Stalborch; Erik T. Valent; Kalim Nawaz; Jan van Bezu; Etto C. Eringa; Femke P. M. Hoevenaars; Iris M. De Cuyper; Peter L. Hordijk; Victor W. M. van Hinsbergh; Geerten P. van Nieuw Amerongen; Jurjan Aman; et al. (Angiogenesis, 2021)
Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak.

Circulating level of Angiopoietin-2 is associated with acute kidney injury in coronavirus disease 2019 (COVID-19) - Brandon Michael Henry; Maria Helena Santos de Oliveira; Isaac Cheruiyot; Justin L. Benoit; David S. Cooper; Giuseppe Lippi; Timothy D. Le Cras; Stefanie W. Benoit (Angiogenesis, 2021)

Hydrogel-mediated delivery of microRNA-92a inhibitor polyplex nanoparticles induces localized angiogenesis - Fatemeh Radmanesh; Hamid Sadeghi Abandansari; Mohammad Hossein Ghanian; Sara Pahlavan; Fahimeh Varzideh; Saeed Yakhkeshi; Mehdi Alikhani; Sharif Moradi; Thomas Braun; Hossein Baharvand (Angiogenesis, 2021)

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression - Delphine M. Lees; Louise E. Reynolds; Ana Rita Pedrosa; Marina Roy-Luzarraga; Kairbaan M. Hodivala-Dilke (Angiogenesis, 2021)
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ; FAK WT/WT , PdgfrβCre + ; FAK Y397F/Y397F and PdgfrβCre + ; FAK Y861F/Y861F mice, our data demonstrate that Lewis lung carcinoma tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ; FAK Y861F/Y861F but not PdgfrβCre + ; FAK Y397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity - Anantha K. Kanugula; Ravi K. Adapala; Anurag Jamaiyar; Nina Lenkey; Brianna D. Guarino; Wolfgang Liedtke; Liya Yin; Sailaja Paruchuri; Charles K. Thodeti (Angiogenesis, 2021)

Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8 - Vivien Becker; Xin Hui; Lisa Nalbach; Emmanuel Ampofo; Peter Lipp; Michael D. Menger; Matthias W. Laschke; Yuan Gu (Angiogenesis, 2021)
Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3 R )-(−)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cytotoxic doses of linalool significantly inhibited HDMEC proliferation, migration, tube formation and spheroid sprouting. Linalool also suppressed the vascular sprouting from rat aortic rings. In addition, Matrigel plugs containing linalool exhibited a significantly reduced microvessel density 7 days after implantation into BALB/c mice. Mechanistic analyses revealed that linalool promotes the phosphorylation of extracellular signal-regulated kinase (ERK), downregulates the intracellular level of adenosine triphosphate (ATP) and activates the transient receptor potential cation channel subfamily M (melastatin) member (TRPM)8 in HDMECs. Inhibition of ERK signaling, supplementation of ATP and blockade of TRPM8 significantly counteracted linalool-suppressed HDMEC spheroid sprouting. Moreover, ATP supplementation completely reversed linalool-induced ERK phosphorylation. In addition, linalool-induced ERK phosphorylation inhibited the expression of bone morphogenetic protein (BMP)-2 and linalool-induced TRPM8 activation caused the inhibition of β1 integrin/focal adhesion kinase (FAK) signaling. These findings indicate an anti-angiogenic effect of linalool, which is mediated by downregulating intracellular ATP levels and activating TRPM8.

Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway - Bing Liu; Han Zhou; Tiening Zhang; Xixiang Gao; Bo Tao; Hao Xing; Zhenwu Zhuang; Alan Dardik; Themis R. Kyriakides; Julie E. Goodwin (Angiogenesis, 2021)
Objective The glucocorticoid receptor (GR) is a member of the nuclear receptor family that controls key biological processes in the cardiovascular system and has recently been shown to modulate Wnt signaling in endothelial cells. Wnt/β-catenin signaling has been demonstrated to be crucial in the process of angiogenesis. In the current study, we studied whether GR could regulate angiogenesis via the Wnt/β-catenin pathway. Approach and Resultsa Key components of the Wnt/β-catenin pathway were evaluated using quantitative PCR and Western blot in the presence or absence of GR. Enhanced angiogenesis was found in GR deficiency in vitro and confirmed with cell viability assays, proliferation assays and tube formation assays. Consistent with these in vitro findings, endothelial cell-specific GR loss GR in vivo promoted angiogenesis in both a hind limb ischemia model and sponge implantation assay. Results were further verified in a novel mouse model lacking endothelial LRP5/6, a key receptor in canonical Wnt signaling, and showed substantially suppressed angiogenesis using these same in vitro and in vivo assays. To further investigate the mechanism of GR regulation of Wnt signaling, autophagy flux was investigated in endothelial cells by visualizing auto phagolysosomes as well as by assessing P62 degradation and LC3B conversion. Results indicated that potentiated autophagy flux participated in GR-Wnt regulation. Conclusions Lack of endothelial GR triggers autophagy flux, leads to activation of Wnt/β-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/β-catenin signaling.

7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment - Haibo Wang; Aniket Ramshekar; Eric Kunz; M. Elizabeth Hartnett (Angiogenesis, 2021)

Dysbiotic stress increases the sensitivity of the tumor vasculature to radiotherapy and c-Met inhibitors - Samir V. Jenkins; Mohammad Alimohammadi; Alexia S. Terry; Robert J. Griffin; Alan J. Tackett; Justin W. Leung; Kieng B. Vang; Stephanie D. Byrum; Ruud P. M. Dings (Angiogenesis, 2021)

Refractory severe idiopathic systemic capillary leak syndrome successfully treated with bevacizumab: a case report - G. Kouadri; N. Perzo; G. Sauvetre; H. Lévesque; E. Besnier (Angiogenesis, 2021)

Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization - Fabiana Baganha; Rob C. M. de Jong; Erna A. Peters; Wietske Voorham; J. Wouter Jukema; Mirela Delibegovic; Margreet R. de Vries; Paul H. A. Quax (Angiogenesis, 2021)
Objective Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin’s lipid-lowering dependent and independent effects on IPA and IPH. Approach and results ApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin’s anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs. Conclusions Atorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.

The DOCK protein family in vascular development and disease - Clare E. Benson; Laura Southgate (Angiogenesis, 2021)
The vascular network is established and maintained through the processes of vasculogenesis and angiogenesis, which are tightly regulated during embryonic and postnatal life. The formation of a functional vasculature requires critical cellular mechanisms, such as cell migration, proliferation and adhesion, which are dependent on the activity of small Rho GTPases, controlled in part by the dedicator of cytokinesis (DOCK) protein family. Whilst the majority of DOCK proteins are associated with neuronal development, a growing body of evidence has indicated that members of the DOCK family may have key functions in the control of vasculogenic and angiogenic processes. This is supported by the involvement of several angiogenic signalling pathways, including chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF) and phosphatidylinositol 3-kinase (PI3K), in the regulation of specific DOCK proteins. This review summarises recent progress in understanding the respective roles of DOCK family proteins during vascular development. We focus on existing in vivo and in vitro models and known human disease phenotypes and highlight potential mechanisms of DOCK protein dysfunction in the pathogenesis of vascular disease.

RSF1 requires CEBP/β and hSNF2H to promote IL-1β-mediated angiogenesis: the clinical and therapeutic relevance of RSF1 overexpression and amplification in myxofibrosarcomas - Chien-Feng Li; Ti-Chen Chan; Cheng-I. Wang; Fu-Min Fang; Po-Chun Lin; Shih-Chen Yu; Hsuan-Ying Huang (Angiogenesis, 2021)

A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner - Xiao-Jing Chen; Wen-Fei Wei; Zi-Ci Wang; Nisha Wang; Chu-Hong Guo; Chen-Fei Zhou; Luo-Jiao Liang; Sha Wu; Li Liang; Wei Wang (Angiogenesis, 2021)
Lymphatic remodelling in the hypoxic tumour microenvironment (TME) is critically involved in the metastasis of cervical squamous cell carcinoma (CSCC); however, its underlying mechanisms remain unclear. Here, we uncovered a novel lymphatic pattern in the hypoxic TME, wherein lymphatic vessels (LVs) are encapsulated by tumour-associated macrophages (TAMs) to form an interconnected network. We describe these aggregates as LVEM (LVs encapsulated by TAMs) considering their advantageous metastatic capacity and active involvement in early lymph node metastasis (LNM). Mechanistic investigations revealed that interleukin-10 (IL-10) derived from hypoxic TAMs adjacent to LVs was a prerequisite for lymphangiogenesis and LVEM formation through its induction of Sp1 upregulation in lymphatic endothelial cells (LECs). Interestingly, Sp1 high LECs promoted the transactivation of C–C motif chemokine ligand 1 (CCL1) to facilitate TAM and tumour cell recruitment, thereby forming a positive feedback loop to strengthen the LVEM formation. Knockdown of Sp1 or blockage of CCL1 abrogated LVEM and consequently attenuated LNM. Notably, CSCC non-LNM is largely devoid of hypoxic TAMs and the resultant LVEM, which might explain its metastatic delay. These findings identify a novel and efficient metastasis-promoting lymphatic pattern in the hypoxic TME, which might provide new targets for anti-metastasis therapy and prognostic assessment.

RIPK3 modulates growth factor receptor expression in endothelial cells to support angiogenesis - Siqi Gao; Courtney T. Griffin (Angiogenesis, 2021)

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality - Aurélien Philippe; Richard Chocron; Nicolas Gendron; Olivier Bory; Agathe Beauvais; Nicolas Peron; Lina Khider; Coralie L. Guerin; Guillaume Goudot; Françoise Levasseur; Christophe Peronino; Jerome Duchemin; et al. (Angiogenesis, 2021)

YAP promotes ocular neovascularization by modifying PFKFB3-driven endothelial glycolysis - Yifan Feng; Rong Zou; Xi Zhang; Minqian Shen; Xiuping Chen; Jing Wang; Weiran Niu; Yuanzhi Yuan; Fei Yuan (Angiogenesis, 2021)

Endothelial cell plasticity at the single-cell level - Alessandra Pasut; Lisa M. Becker; Anne Cuypers; Peter Carmeliet (Angiogenesis, 2021)
The vascular endothelium is characterized by a remarkable level of plasticity, which is the driving force not only of physiological repair/remodeling of adult tissues but also of pathological angiogenesis. The resulting heterogeneity of endothelial cells (ECs) makes targeting the endothelium challenging, no less because many EC phenotypes are yet to be identified and functionally inventorized. Efforts to map the vasculature at the single-cell level have been instrumental to capture the diversity of EC types and states at a remarkable depth in both normal and pathological states. Here, we discuss new EC subtypes and functions emerging from recent single-cell studies in health and disease. Interestingly, such studies revealed distinct metabolic gene signatures in different EC phenotypes, which deserve further consideration for therapy. We highlight how this metabolic targeting strategy could potentially be used to promote (for tissue repair) or block (in tumor) angiogenesis in a tissue or even vascular bed-specific manner.

Angiogenesis: a year in review - Arjan W. Griffioen; Andrew C. Dudley (Angiogenesis, 2021)

Role of Notch in endothelial biology - Macarena Fernández-Chacón; Irene García-González; Severin Mühleder; Rui Benedito (Angiogenesis, 2021)

Endothelial heterogeneity and plasticity - Coert Margadant (Angiogenesis, 2021)

Vascular endothelial cell specification in health and disease - Corina Marziano; Gael Genet; Karen K. Hirschi (Angiogenesis, 2021)
There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

Adieu to parting Editor in Chief and pioneering scientist Dr. Joyce Bischoff - Juan M. Melero-Martin; Andrew C. Dudley; Arjan W. Griffioen (Angiogenesis, 2021)

Mechanisms and cell lineages in lymphatic vascular development - Daniyal J. Jafree; David A. Long; Peter J. Scambler; Christiana Ruhrberg (Angiogenesis, 2021)
Lymphatic vessels have critical roles in both health and disease and their study is a rapidly evolving area of vascular biology. The consensus on how the first lymphatic vessels arise in the developing embryo has recently shifted. Originally, they were thought to solely derive by sprouting from veins. Since then, several studies have uncovered novel cellular mechanisms and a diversity of contributing cell lineages in the formation of organ lymphatic vasculature. Here, we review the key mechanisms and cell lineages contributing to lymphatic development, discuss the advantages and limitations of experimental techniques used for their study and highlight remaining knowledge gaps that require urgent attention. Emerging technologies should accelerate our understanding of how lymphatic vessels develop normally and how they contribute to disease.

First blood: the endothelial origins of hematopoietic progenitors - Giovanni Canu; Christiana Ruhrberg (Angiogenesis, 2021)
Hematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

SMAD6 transduces endothelial cell flow responses required for blood vessel homeostasis - Dana L. Ruter; Ziqing Liu; Kimlynn M. Ngo; Shaka X; Allison Marvin; Danielle B. Buglak; Elise J. Kidder; Victoria L. Bautch (Angiogenesis, 2021)
Fluid shear stress provided by blood flow instigates a transition from active blood vessel network expansion during development, to vascular homeostasis and quiescence that is important for mature blood vessel function. Here we show that SMAD6 is required for endothelial cell flow-mediated responses leading to maintenance of vascular homeostasis. Concomitant manipulation of the mechanosensor Notch1 pathway and SMAD6 expression levels revealed that SMAD6 functions downstream of ligand-induced Notch signaling and transcription regulation. Mechanistically, full-length SMAD6 protein was needed to rescue Notch loss-induced flow misalignment. Endothelial cells depleted for SMAD6 had defective barrier function accompanied by upregulation of proliferation-associated genes and down regulation of junction-associated genes. The vascular protocadherin PCDH12 was upregulated by SMAD6 and required for proper flow-mediated endothelial cell alignment, placing it downstream of SMAD6. Thus, SMAD6 is a required transducer of flow-mediated signaling inputs downstream of Notch1 and upstream of PCDH12, as vessels transition from an angiogenic phenotype to maintenance of a homeostatic phenotype.

Angiodiversity and organotypic functions of sinusoidal endothelial cells - Philipp-Sebastian Koch; Ki Hong Lee; Sergij Goerdt; Hellmut G. Augustin (Angiogenesis, 2021)
‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.

The adaptor protein Grb2b is an essential modulator for lympho-venous sprout formation in the zebrafish trunk - Cristina Mauri; Andreas van Impel; Eirinn William Mackay; Stefan Schulte-Merker (Angiogenesis, 2021)
Vegfc/Vegfr3 signaling is critical for lymphangiogenesis, the sprouting of lymphatic vessels. In zebrafish, cells sprouting from the posterior cardinal vein can either form lymphatic precursor cells or contribute to intersegmental vein formation. Both, the Vegfc-dependent differential induction of Prox1a in sprouting cells as well as a Notch-mediated pre-pattern within intersegmental vessels have been associated with the regulation of secondary sprout behavior. However, how exactly a differential lymphatic versus venous sprout cell behavior is achieved is not fully understood. Here, we characterize a zebrafish mutant in the adaptor protein Grb2b, and demonstrate through genetic interaction studies that Grb2b acts within the Vegfr3 pathway. Mutant embryos exhibit phenotypes that are consistent with reduced Vegfr3 signaling outputs prior to the sprouting of endothelial cells from the vein. During secondary sprouting stages, loss of grb2b leads to defective cell behaviors resulting in a loss of parachordal lymphangioblasts, while only partially affecting the number of intersegmental veins. A second GRB2 zebrafish ortholog, grb2a , contributes to the development of lymphatic structures in the meninges and in the head, but not in the trunk. Our results illustrate an essential role of Grb2b in vivo for cell migration to the horizontal myoseptum and for the correct formation of the lymphatic vasculature, while being less critically required in intersegmental vein formation. Thus, there appear to be higher requirements for Grb2b and therefore Vegfr3 downstream signaling levels in lymphatic versus vein precursor-generating sprouts.

Human endothelial colony-forming cells provide trophic support for pluripotent stem cell-derived cardiomyocytes via distinctively high expression of neuregulin-1 - Xuechong Hong; Nicholas Oh; Kai Wang; Joseph Neumeyer; Chin Nien Lee; Ruei-Zeng Lin; Breanna Piekarski; Sitaram Emani; Arin K. Greene; Ingeborg Friehs; Pedro J. del Nido; Juan M. Melero-Martin (Angiogenesis, 2021)

To be or not to be: endothelial cell plasticity in development, repair, and disease - Leah J. Greenspan; Brant M. Weinstein (Angiogenesis, 2021)

Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study - S. Kroon; R. J. Snijder; A. E. Hosman; V. M.M. Vorselaars; F. J.M Disch; M. C. Post; J. J. Mager (Angiogenesis, 2021)

Endothelium-specific deletion of Nox4 delays retinal vascular development and mitigates pathological angiogenesis - Xixiang Tang; Joshua J. Wang; Jinli Wang; Hanna E. Abboud; Yanming Chen; Sarah X. Zhang (Angiogenesis, 2021)

Protection of capillaries may be critical in delaying aging around the eyes and prevention of facial plastic surgery - Pengfei Sun; Di Xu; Fang Luan (Angiogenesis, 2021)

Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis - Fadi E. Pulous; Jamie C. Carnevale; Zaki Al-Yafeai; Brenna H. Pearson; Jamie A. G. Hamilton; Curtis J. Henry; A. Wayne Orr; Brian G. Petrich (Angiogenesis, 2021)

Microvascular dysfunction in COVID-19: the MYSTIC study - Alexandros Rovas; Irina Osiaevi; Konrad Buscher; Jan Sackarnd; Phil-Robin Tepasse; Manfred Fobker; Joachim Kühn; Stephan Braune; Ulrich Göbel; Gerold Thölking; Andreas Gröschel; Hermann Pavenstädt; et al. (Angiogenesis, 2021)
Rationale Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. Objectives To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. Methods Hospitalized adult patients with moderate-to-severe or critical COVID-19 ( n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity ( V RBC ), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. Measurements and main results COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of V RBC . Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. Conclusions Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19 - Antoni Riera-Mestre; Adriana Iriarte; Manuela Moreno; Raul del Castillo; Daniel López-Wolf (Angiogenesis, 2021)
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registry including adult patients with HHT. A 27-item survey that captured clinical data of admitted HHT patients for COVID-19 was distributed to all RiHHTa investigators from June 8th to June 24th 2020. Only one out of 1177 HHT patients was admitted for COVID-19 pneumonia. She is a 74 years-old woman with a pathogenic variant in ACVRL1 gene. Her clinical course did not involve mechanical ventilation or worsening epistaxis, and she was successfully discharged after two weeks. The endothelial damage and the consequent angiogenic process in COVID-19 patients deserve further investigation.

Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors - Miho Kobayashi; Ikumi Wakabayashi; Yasuhiro Suzuki; Kashio Fujiwara; Masanori Nakayama; Tetsuro Watabe; Yasufumi Sato (Angiogenesis, 2021)

3D analysis of microvasculature in murine liver fibrosis models using synchrotron radiation-based microtomography - Willi L. Wagner; Sonja Föhst; Jessica Hock; Yong Ook Kim; Yury Popov; Detlef Schuppan; Katja Schladitz; Claudia Redenbach; Maximilian Ackermann (Angiogenesis, 2021)
Cirrhosis describes the development of excess fibrous tissue around regenerative nodules in response to chronic liver injury and usually leads to irreversible organ damage and end-stage liver disease. During the development of cirrhosis, the formation of collagenous scar tissue is paralleled by a reorganization and remodeling of the hepatic vascular system. To date, macrovascular remodeling in various cirrhosis models has been examined using three-dimensional (3D) imaging modalities, while microvascular changes have been studied mainly by two-dimensional (2D) light microscopic and electron microscopic imaging. Here, we report on the application of high-resolution 3D synchrotron radiation-based microtomography (SRμCT) for the study of the sinusoidal and capillary blood vessel system in three murine models of advanced parenchymal and biliary hepatic fibrosis. SRμCT facilitates the characterization of microvascular architecture and identifies features of intussusceptive angiogenesis in progressive liver fibrosis in a non-destructive 3D manner.

Vessel tech: a high-accuracy pipeline for comprehensive mouse retinal vasculature characterization - Xuelin Wang; Guofu Zhu; Shumin Wang; Jordan Rhen; Jinjiang Pang; Zhengwu Zhang (Angiogenesis, 2021)

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF - H. H. Pulkkinen; M. Kiema; J. P. Lappalainen; A. Toropainen; M. Beter; A. Tirronen; L. Holappa; H. Niskanen; M. U. Kaikkonen; S. Ylä-Herttuala; Johanna P. Laakkonen (Angiogenesis, 2021)
The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.

Piwi-interacting RNAs (piRNAs) as potential biomarkers and therapeutic targets for cardiovascular diseases - Min Li; Yanyan Yang; Zhibin Wang; Tingyu Zong; Xiuxiu Fu; Lynn Htet Htet Aung; Kun Wang; Jian-xun Wang; Tao Yu (Angiogenesis, 2021)

Characterization of a neutralizing anti-human galectin-1 monoclonal antibody with angioregulatory and immunomodulatory activities - Juan M. Pérez Sáez; Pablo F. Hockl; Alejando J. Cagnoni; Santiago P. Méndez Huergo; Pablo A. García; Sabrina G. Gatto; Juan P. Cerliani; Diego O. Croci; Gabriel A. Rabinovich (Angiogenesis, 2021)

AgeR deletion decreases soluble fms-like tyrosine kinase 1 production and improves post-ischemic angiogenesis in uremic mice - Vincent Dupont; Rida Al-Rifai; Gael Poitevin; Jeremy Ortillon; Laura Jayyosi; Christine Terryn; Caroline Francois; Philippe Rieu; Günter Fritz; Camile Boulagnon-Rombi; Caroline Fichel; Ann Marie Schmidt; et al. (Angiogenesis, 2021)

Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes - Jing Bai; Mehrdad Khajavi; Lufei Sui; Haojie Fu; Subrahmanian Tarakkad Krishnaji; Amy E. Birsner; Lauren Bazinet; Roger D. Kamm; Robert J. D’Amato (Angiogenesis, 2021)

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization - Jinying Chen; Fan-Li Lin; Jacqueline Y. K. Leung; Leilei Tu; Jiang-Hui Wang; Yu-Fan Chuang; Fan Li; Hsin-Hui Shen; Gregory J. Dusting; Vickie H. Y. Wong; Leszek Lisowski; Alex W. Hewitt; et al. (Angiogenesis, 2021)

RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway - Kailiang Qiao; Yantao Liu; Zheng Xu; Haohao Zhang; Heng Zhang; Chao Zhang; Zhi Chang; Xinyan Lu; Zhongwei Li; Ce Luo; Yanrong Liu; Cheng Yang; et al. (Angiogenesis, 2021)

Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice - Quang Linh Nguyen; Noriko Okuno; Takeru Hamashima; Son Tung Dang; Miwa Fujikawa; Yoko Ishii; Atsushi Enomoto; Takakuni Maki; Hoang Ngoc Nguyen; Van Tuyen Nguyen; Toshihiko Fujimori; Hisashi Mori; et al. (Angiogenesis, 2021)

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells - Carlotta Tacconi; Yuliang He; Luca Ducoli; Michael Detmar (Angiogenesis, 2021)
Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the transcriptomic landscapes, histone composition (H3K4me3 and H3K27me3) and DNA methylomes of cultured matched human primary dermal lymphatic and blood vascular ECs. Our findings reveal that blood vascular lineage genes manifest a more ‘repressed’ histone composition in lymphatic ECs, whereas DNA methylation at promoters is less linked to the differential transcriptomes of lymphatic versus blood vascular ECs. Meta-analyses identified two transcriptional regulators, BCL6 and MEF2C, which potentially govern endothelial lineage specificity. Notably, the blood vascular endothelial lineage markers CD34, ESAM and FLT1 and the lymphatic endothelial lineage markers PROX1, PDPN and FLT4 exhibited highly differential epigenetic profiles and responded in distinct manners to epigenetic drug treatments. The perturbation of histone and DNA methylation selectively promoted the expression of blood vascular endothelial markers in lymphatic endothelial cells, but not vice versa. Overall, our study reveals that the fine regulation of lymphatic and blood vascular endothelial transcriptomes is maintained via several epigenetic mechanisms, which are crucial to the maintenance of endothelial cell identity.

Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells - Robert Szulcek; Gonzalo Sanchez-Duffhues; Nina Rol; Xiaoke Pan; Roula Tsonaka; Chris Dickhoff; Lai Ming Yung; Xue D. Manz; Kondababu Kurakula; Szymon M. Kiełbasa; Hailiang Mei; Wim Timens; et al. (Angiogenesis, 2020)
Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6.

IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation - Haibo Wang; Aniket Ramshekar; Eric Kunz; David B. Sacks; M. Elizabeth Hartnett (Angiogenesis, 2020)

Leopold Auerbach’s achievements in the field of vascular system - Andrzej Wincewicz; Piotr Woltanowski (Angiogenesis, 2020)

Novel Murine Models of Cerebral Cavernous Malformations - Matthew R. Detter; Robert Shenkar; Christian R. Benavides; Catherine A. Neilson; Thomas Moore; Rhonda Lightle; Nicholas Hobson; Le Shen; Ying Cao; Romuald Girard; Dongdong Zhang; Erin Griffin; et al. (Angiogenesis, 2020)

Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity - Eri Watanabe; Tsutomu Wada; Akira Okekawa; Fuka Kitamura; Go Komatsu; Yasuhiro Onogi; Seiji Yamamoto; Masakiyo Sasahara; Munehiro Kitada; Daisuke Koya; Hiroshi Tsuneki; Toshiyasu Sasaoka (Angiogenesis, 2020)

Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions - Danielle B. Buglak; Erich J. Kushner; Allison P. Marvin; Katy L. Davis; Victoria L. Bautch (Angiogenesis, 2020)
Proper blood vessel formation requires coordinated changes in endothelial cell polarity and rearrangement of cell–cell junctions to form a functional lumen. One important regulator of cell polarity is the centrosome, which acts as a microtubule organizing center. Excess centrosomes perturb aspects of endothelial cell polarity linked to migration, but whether centrosome number influences apical–basal polarity and cell–cell junctions is unknown. Here, we show that excess centrosomes alter the apical–basal polarity of endothelial cells in angiogenic sprouts and disrupt endothelial cell–cell adherens junctions. Endothelial cells with excess centrosomes had narrower lumens in a 3D sprouting angiogenesis model, and zebrafish intersegmental vessels had reduced perfusion following centrosome overduplication. These results indicate that endothelial cell centrosome number regulates proper lumenization downstream of effects on apical–basal polarity and cell–cell junctions. Endothelial cells with excess centrosomes are prevalent in tumor vessels, suggesting how centrosomes may contribute to tumor vessel dysfunction.

Are antiangiogenics a good ‘partner’ for immunotherapy in ovarian cancer? - Elena García-Martínez; Andres Redondo; Josep Maria Piulats; Analía Rodríguez; Antonio Casado (Angiogenesis, 2020)
Ovarian cancer (OC) is associated with poor survival because there are a limited number of effective therapies. Two processes key to OC progression, angiogenesis and immune evasion, act synergistically to promote tumor progression. Tumor-associated angiogenesis promotes immune evasion, and tumor-related immune responses in the peritoneal cavity and tumor microenvironment (TME) affect neovascular formation. Therefore, suppressing the angiogenic pathways could facilitate the arrival of immune effector cells and reduce the presence of myeloid cells involved in immune suppression. To date, clinical studies have shown significant benefits with antiangiogenic therapy as first-line therapy in OC, as well as in recurrent disease, and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab is now an established therapy. Clinical data with immunomodulators in OC are more limited, but suggest that they could benefit some patients with recurrent disease. The preliminary results of two phase III trials have shown that the addition of immunomodulators to chemotherapy does not improve progression-free survival. For this reason, it could be interesting to look for synergistic effects between immunomodulators and other active drugs in OC. Since bevacizumab is approved for use in OC, and is tolerable when used in combination with immunotherapy in other indications, a number of clinical studies are underway to investigate the use of bevacizumab in combination with immunotherapeutic agents in OC. This strategy seeks to normalize the TME via the anti-VEGF actions of bevacizumab, while simultaneously stimulating the immune response via the immunotherapy. Results of these studies are awaited with interest.

Pleiotrophin selectively binds to vascular endothelial growth factor receptor 2 and inhibits or stimulates cell migration depending on ανβ3 integrin expression - Margarita Lamprou; Pinelopi Kastana; Fani Kofina; Ηaralampos Tzoupis; Spyridoula Barmpoutsi; Md Sanaullah Sajib; Marina Koutsioumpa; Evangelia Poimenidi; Aikaterini A. Zompra; Dimitrios Tassopoulos; Effrosyni Choleva; Theodore Tselios; et al. (Angiogenesis, 2020)

Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model - Victoria H. Ko; Lumeng J. Yu; Duy T. Dao; Xiaoran Li; Jordan D. Secor; Lorenzo Anez-Bustillos; Bennet S. Cho; Amy Pan; Paul D. Mitchell; Hiroko Kishikawa; Mark Puder (Angiogenesis, 2020)

Embryonic circulating endothelial progenitor cells - Sandra Díaz del Moral; Silvia Barrena; Ramón Muñoz-Chápuli; Rita Carmona (Angiogenesis, 2020)

Arterial endoglin does not protect against arteriovenous malformations - Esha Singh; Rachael E. Redgrave; Helen M. Phillips; Helen M. Arthur (Angiogenesis, 2020)
Introduction Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder hereditary haemorrhagic telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation, we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. Methods Using the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which Apj-Cre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following pan-endothelial or venous/capillary-specific ENG knockout. Results Activation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature. Conclusion Expression of ENG is not required in arterial ECs to protect against AVM formation.

Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients - David M. Smadja; Coralie L. Guerin; Richard Chocron; Nader Yatim; Jeremy Boussier; Nicolas Gendron; Lina Khider; Jérôme Hadjadj; Guillaume Goudot; Benjamin Debuc; Philippe Juvin; Caroline Hauw-Berlemont; et al. (Angiogenesis, 2020)

B-cell non-Hodgkin lymphoma: importance of angiogenesis and antiangiogenic therapy - Lei Jiang; Nailin Li (Angiogenesis, 2020)

Heterogeneity and chimerism of endothelial cells revealed by single-cell transcriptome in orthotopic liver tumors - Qi Zhao; Maria del Pilar Molina-Portela; Asma Parveen; Alexander Adler; Christina Adler; Hock E; Wei Wang; Min Ni; Yi Wei; Gurinder Atwal; Markus Mohrs; Gavin Thurston; et al. (Angiogenesis, 2020)
The liver is a common host organ for cancer, either through lesions that arise in liver epithelial cells [e.g., hepatocellular carcinoma (HCC)] or as a site of metastasis by tumors arising in other organs (e.g., colorectal cancer). However, the changes that occur in liver stromal cells in response to cancer have not been fully characterized, nor has it been determined whether the different sources of liver cancer induce distinct stromal changes. Here, we performed single-cell profiling of liver stromal cells from mouse models of induced spontaneous liver cancer or implanted colorectal liver metastases, with a focus on tumor endothelial cells (ECs). While ECs in liver tissue adjacent to cancerous lesions (so-called adjacent normal) corresponded to liver zonation phenotypes, their transcriptomes were also clearly altered by the presence of a tumor. In comparison, tumor EC transcriptomes show stronger similarities to venous than sinusoidal ECs. Further, tumor ECs, independent of tumor origin, formed distinct clusters displaying conserved “tip-like” or “stalk-like” characteristics, similar to ECs from subcutaneous tumors. However, they also carried liver-specific signatures found in normal liver ECs, suggesting an influence of the host organ on tumor ECs. Our results document gene expression signatures in ECs in liver cancer and show that the host organ, and not the site of tumor origin (liver versus colorectal), is a primary determinant of EC phenotype. In addition, primarily in tumors, we further defined a cluster of chimeric cells that expressed both myeloid and endothelial cell markers and might play a role in tumor angiogenesis.

Tumor-derived exosomes promote angiogenesis via adenosine A2B receptor signaling - Nils Ludwig; Saigopalakrishna S. Yerneni; Juliana H. Azambuja; Delbert G. Gillespie; Elizabeth V. Menshikova; Edwin K. Jackson; Theresa L. Whiteside (Angiogenesis, 2020)

RHOQ is induced by DLL4 and regulates angiogenesis by determining the intracellular route of the Notch intracellular domain - Esther Bridges; Helen Sheldon; Esther Kleibeuker; Evelyn Ramberger; Christos Zois; Alun Barnard; Ulrike Harjes; Ji-Liang Li; Massimo Masiero; Robert MacLaren; Adrian Harris (Angiogenesis, 2020)
Angiogenesis, the formation of new blood vessels by endothelial cells, is a finely tuned process relying on the balance between promoting and repressing signalling pathways. Among these, Notch signalling is critical in ensuring appropriate response of endothelial cells to pro-angiogenic stimuli. However, the downstream targets and pathways effected by Delta-like 4 (DLL4)/Notch signalling and their subsequent contribution to angiogenesis are not fully understood. We found that the Rho GTPase, RHOQ, is induced by DLL4 signalling and that silencing RHOQ results in abnormal sprouting and blood vessel formation both in vitro and in vivo. Loss of RHOQ greatly decreased the level of Notch signalling, conversely overexpression of RHOQ promoted Notch signalling. We describe a new feed-forward mechanism regulating DLL4/Notch signalling, whereby RHOQ is induced by DLL4/Notch and is essential for the NICD nuclear translocation. In the absence of RHOQ, Notch1 becomes targeted for degradation in the autophagy pathway and NICD is sequestered from the nucleus and targeted for degradation in lysosomes.

Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer - Dirk Bausch; Stefan Fritz; Louisa Bolm; Ulrich F. Wellner; Carlos Fernandez-del-Castillo; Andrew L. Warshaw; Sarah P. Thayer; Andrew S. Liss (Angiogenesis, 2020)

Endothelial deletion of ADAM10, a key regulator of Notch signaling, causes impaired decidualization and reduced fertility in female mice - Nicole Lustgarten Guahmich; Gregory Farber; Shiva Shafiei; Dylan McNally; David Redmond; Eleni Kallinos; Heidi Stuhlmann; Daniel Dufort; Daylon James; Carl P. Blobel (Angiogenesis, 2020)

Simultaneous fluorescence imaging of distinct nerve and blood vessel patterns in dual Thy1-YFP and Flt1-DsRed transgenic mice - Samuel M. Santosa; Kai Guo; Michael Yamakawa; Evguenia Ivakhnitskaia; Neeraj Chawla; Tara Nguyen; Kyu-Yeon Han; Masatsugu Ema; Mark I. Rosenblatt; Jin-Hong Chang; Dimitri T. Azar (Angiogenesis, 2020)

Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation - Timothy D. Le Cras; Jillian Goines; Nora Lakes; Patricia Pastura; Adrienne M. Hammill; Denise M. Adams; Elisa Boscolo (Angiogenesis, 2020)

Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself - Qian-Kun Yang; Tong Chen; Shi-Qi Wang; Xiao-Jing Zhang; Zhong-Xiang Yao (Angiogenesis, 2020)

Lymphatic MAFB regulates vascular patterning during developmental and pathological lymphangiogenesis - Lothar C. Dieterich; Carlotta Tacconi; Franziska Menzi; Steven T. Proulx; Kübra Kapaklikaya; Michito Hamada; Satoru Takahashi; Michael Detmar (Angiogenesis, 2020)
MAFB is a transcription factor involved in the terminal differentiation of several cell types, including macrophages and keratinocytes. MAFB is also expressed in lymphatic endothelial cells (LECs) and is upregulated by VEGF-C/VEGFR-3 signaling. Recent studies have revealed that MAFB regulates several genes involved in lymphatic differentiation and that global Mafb knockout mice show defects in patterning of lymphatic vessels during embryogenesis. However, it has remained unknown whether this effect is LEC-intrinsic and whether MAFB might also be involved in postnatal lymphangiogenesis. We established conditional, lymphatic-specific Mafb knockout mice and found comparable lymphatic patterning defects during embryogenesis as in the global MAFB knockout. Lymphatic MAFB deficiency resulted in increased lymphatic branching in the diaphragm at P7, but had no major effect on lymphatic patterning or function in healthy adult mice. By contrast, tumor-induced lymphangiogenesis was enhanced in mice lacking lymphatic MAFB. Together, these data reveal that LEC-expressed MAFB is involved in lymphatic vascular morphogenesis during embryonic and postnatal development as well as in pathological conditions. Therefore, MAFB could represent a target for therapeutic modulation of lymphangiogenesis.

Raftlin is recruited by neuropilin-1 to the activated VEGFR2 complex to control proangiogenic signaling - Asha L. Bayliss; Ananthalakshmy Sundararaman; Camille Granet; Harry Mellor (Angiogenesis, 2020)
Background VEGFR2 (vascular endothelial growth factor receptor 2) is the major pro-angiogenic receptor in endothelial cells. Compared to other members of the receptor tyrosine kinase family, we know relatively few VEGFR2 signaling partners. Our objective was to use mass spectrometry-based proteomics to identify novel binding partners of activated VEGFR2. Methods We created an endothelial cell line stably expressing GFP-tagged VEGFR2 and isolated activated receptor complexes. Analysis by mass spectrometry identified raftlin as a novel binding partner of VEGFR2. Results We found that raftlin is recruited to the activated VEGFR2 complex via the co-receptor Nrp1 (neuropilin-1). We show that raftlin regulates the surface levels of Nrp1 in endothelial cells, controlling the availability of Nrp1 for VEGFR2 interaction. Raftlin stabilizes active VEGFR2 at the cell surface by inhibiting endocytosis of the activated receptor. Raftlin also promotes recycling of internalized VEGFR2 to the cell surface. Raftlin alters the signaling outcomes of VEGFR2 activation, inhibiting the activation of p38 and FAK (focal adhesion kinases) specifically. Both pathways are linked to cell migration in endothelial cells, and raftlin inhibits endothelial cell migration in response to VEGF. Conclusion Nrp1 is an important co-receptor for VEGFR2; however, its functions are still only partially understood. We show that raftlin works with Nrp1 in endothelial cells to control intracellular trafficking of the activated VEGFR2. This modulates the response to VEGF and controls endothelial cell migration.

New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury - Jin Wang; Sam Toan; Hao Zhou (Angiogenesis, 2020)

Angiostatic effects of ascorbic acid: current status and future perspectives - Muhammad Torequl Islam (Angiogenesis, 2020)

Lymphangiogenesis and accumulation of reparative macrophages contribute to liver repair after hepatic ischemia–reperfusion injury - Shuji Nakamoto; Yoshiya Ito; Nobuyuki Nishizawa; Takuya Goto; Ken Kojo; Yusuke Kumamoto; Masahiko Watanabe; Masataka Majima (Angiogenesis, 2020)

d-Peptide analogues of Boc-Phe-Leu-Phe-Leu-Phe-COOH induce neovascularization via endothelial N-formyl peptide receptor 3 - Mohd I. Nawaz; Sara Rezzola; Chiara Tobia; Daniela Coltrini; Mirella Belleri; Stefania Mitola; Michela Corsini; Annamaria Sandomenico; Andrea Caporale; Menotti Ruvo; Marco Presta (Angiogenesis, 2020)

Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice - Yohei Tomita; Bertan Cakir; Chi-Hsiu Liu; Zhongjie Fu; Shuo Huang; Steve S. Cho; William R. Britton; Ye Sun; Mark Puder; Ann Hellström; Saswata Talukdar; Lois E. H. Smith (Angiogenesis, 2020)

Intranasal Efudix reduces epistaxis in hereditary hemorrhagic telangiectasia - D. V. C. de Jel; F. J. M. Disch; S. Kroon; J. J. Mager; F. J. Verdam (Angiogenesis, 2020)

TMEM100 is a key factor for specification of lymphatic endothelial progenitors - Eun-Hye Moon; Yong Hwan Kim; Phuong-Nhung Vu; Hyunjin Yoo; Kwonho Hong; Young Jae Lee; S. Paul Oh (Angiogenesis, 2020)

Decylubiquinone suppresses breast cancer growth and metastasis by inhibiting angiogenesis via the ROS/p53/ BAI1 signaling pathway - Jinghua Cao; Xiaohua Liu; Yang Yang; Bo Wei; Qianming Li; Guanquan Mao; Yajun He; Yuanyuan Li; Lingyun Zheng; Qianqian Zhang; Jiangchao Li; Lijing Wang; et al. (Angiogenesis, 2020)

Matrix deformations around angiogenic sprouts correlate to sprout dynamics and suggest pulling activity - Marie-Mo Vaeyens; Alvaro Jorge-Peñas; Jorge Barrasa-Fano; Christian Steuwe; Tommy Heck; Peter Carmeliet; Maarten Roeffaers; Hans Van Oosterwyck (Angiogenesis, 2020)

Retraction Note to: Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression - Hua Zhou; Nada O. Binmadi; Ying-Hua Yang; Patrizia Proia; John R. Basile (Angiogenesis, 2020)

Retraction Note to: The Semaphorin 4D-Plexin-B1-RhoA signaling axis recruits pericytes and regulates vascular permeability through endothelial production of PDGF-B and ANGPTL4 - Hua Zhou; Ying-Hua Yang; John R. Basile (Angiogenesis, 2020)

Correction to: Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D - Nada O. Binmadi; Patrizia Proia; Hua Zhou; Ying-Hua Yang; John R. Basile (Angiogenesis, 2020)

Positive and negative feedback mechanisms controlling tip/stalk cell identity during sprouting angiogenesis - Coert Margadant (Angiogenesis, 2020)

Age-related structural alterations of skeletal muscles and associated capillaries - Kaedeko Fukada; Kentaro Kajiya (Angiogenesis, 2020)

Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation - Alison Domingues; Catherine Boisson-Vidal; Perrine Marquet de Rouge; Blandine Dizier; Jérémy Sadoine; Virginie Mignon; Emilie Vessières; Daniel Henrion; Virginie Escriou; Pascal Bigey; Catherine Chaussain; David M. Smadja; et al. (Angiogenesis, 2020)

Continuous endoglin (CD105) overexpression disrupts angiogenesis and facilitates tumor cell metastasis - Claudia Ollauri-Ibáñez; Elena Núñez-Gómez; Cristina Egido-Turrión; Laura Silva-Sousa; Elena Díaz-Rodríguez; Alicia Rodríguez-Barbero; José M. López-Novoa; Miguel Pericacho (Angiogenesis, 2020)
Endoglin (CD105) is an auxiliary receptor for members of the TFG-β superfamily. Whereas it has been demonstrated that the deficiency of endoglin leads to minor and defective angiogenesis, little is known about the effect of its increased expression, characteristic of several types of cancer. Angiogenesis is essential for tumor growth, so high levels of proangiogenic molecules, such as endoglin, are supposed to be related to greater tumor growth leading to a poor cancer prognosis. However, we demonstrate here that endoglin overexpression do not stimulate sprouting or vascularization in several in vitro and in vivo models. Instead, steady endoglin overexpression keep endothelial cells in an active phenotype that results in an impairment of the correct stabilization of the endothelium and the recruitment of mural cells. In a context of continuous enhanced angiogenesis, such as in tumors, endoglin overexpression gives rise to altered vessels with an incomplete mural coverage that permit the extravasation of blood. Moreover, these alterations allow the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.

Impaired vascular endothelial growth factor expression and secretion during in vitro differentiation of human primary term cytotrophoblasts - Christophe Louis Depoix; Arthur Colson; Corinne Hubinont; Frederic Debieve (Angiogenesis, 2020)

Role of VEGFs in metabolic disorders - M. di Somma; M. Vliora; E. Grillo; B. Castro; E. Dakou; W. Schaafsma; J. Vanparijs; M. Corsini; C. Ravelli; E. Sakellariou; S. Mitola (Angiogenesis, 2020)

The potassium channel Kcne3 is a VEGFA-inducible gene selectively expressed by vascular endothelial tip cells - Ron A. Deckelbaum; Ivan B. Lobov; Eunice Cheung; Gabor Halasz; Saathyaki Rajamani; Julia Lerner; Chunxiang Tong; Zhe Li; Patricia Boland; Melissa Dominguez; Virginia Hughes; George D. Yancopoulos; et al. (Angiogenesis, 2020)
Angiogenesis is largely driven by motile endothelial tip-cells capable of invading avascular tissue domains and enabling new vessel formation. Highly responsive to Vascular Endothelial Growth-Factor-A (VEGFA), endothelial tip-cells also suppress angiogenic sprouting in adjacent stalk cells, and thus have been a primary therapeutic focus in addressing neovascular pathologies. Surprisingly, however, there remains a paucity of specific endothelial tip-cell markers. Here, we employ transcriptional profiling and a lacZ reporter allele to identify Kcne3 as an early and selective endothelial tip-cell marker in multiple angiogenic contexts. In development, Kcne3 expression initiates during early phases of angiogenesis (E9) and remains specific to endothelial tip-cells, often adjacent to regions expressing VEGFA. Consistently, Kcne3 activation is highly responsive to exogenous VEGFA but maintains tip-cell specificity throughout normal retinal angiogenesis. We also demonstrate endothelial tip-cell selectivity of Kcne3 in several injury and tumor models. Together, our data show that Kcne3 is a unique marker of sprouting angiogenic tip-cells and offers new opportunities for investigating and targeting this cell type.

BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance - Teresa L. Capasso; Bijun Li; Harry J. Volek; Waqas Khalid; Elizabeth R. Rochon; Arulselvi Anbalagan; Chelsea Herdman; H. Joseph Yost; Flordeliza S. Villanueva; Kang Kim; Beth L. Roman (Angiogenesis, 2020)

Prognostic value of CEC count in HER2-negative metastatic breast cancer patients treated with bevacizumab and chemotherapy: a prospective validation study (UCBG COMET) - Antoine Vasseur; Luc Cabel; Olivier Tredan; Marion Chevrier; Coraline Dubot; Véronique Lorgis; William Jacot; Anthony Goncalves; Marc Debled; Christelle Levy; Jean-Marc Ferrero; Christelle Jouannaud; et al. (Angiogenesis, 2020)

Reconciling the distinct roles of angiogenic/anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies - Anandita Umapathy; Lawrence W. Chamley; Joanna L. James (Angiogenesis, 2020)

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer - Daniela Unterleuthner; Patrick Neuhold; Katharina Schwarz; Lukas Janker; Benjamin Neuditschko; Harini Nivarthi; Ilija Crncec; Nina Kramer; Christine Unger; Markus Hengstschläger; Robert Eferl; Richard Moriggl; et al. (Angiogenesis, 2020)
WNT2 acts as a pro-angiogenic factor in placental vascularization and increases angiogenesis in liver sinusoidal endothelial cells (ECs) and other ECs. Increased WNT2 expression is detectable in many carcinomas and participates in tumor progression. In human colorectal cancer (CRC), WNT2 is selectively elevated in cancer-associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer, angiogenesis was not addressed so far. We demonstrate that WNT2 enhances EC migration/invasion, while it induces canonical WNT signaling in a small subset of cells. Knockdown of WNT2 in CAFs significantly reduced angiogenesis in a physiologically relevant assay, which allows precise assessment of key angiogenic properties. In line with these results, expression of WNT2 in otherwise WNT2-devoid skin fibroblasts led to increased angiogenesis. In CRC xenografts, WNT2 overexpression resulted in enhanced vessel density and tumor volume. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs by mass spectrometry and cytokine arrays revealed that proteins associated with pro-angiogenic functions are elevated by WNT2. These included extracellular matrix molecules, ANG-2, IL-6, G-CSF, and PGF. The latter three increased angiogenesis. Thus, stromal-derived WNT2 elevates angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.

Role of melatonin in controlling angiogenesis under physiological and pathological conditions - Qiang Ma; Russel J. Reiter; Yundai Chen (Angiogenesis, 2020)

The protein tyrosine phosphatase PTPRJ/DEP-1 contributes to the regulation of the Notch-signaling pathway and sprouting angiogenesis - Patrick Fournier; Claire Viallard; Agnieszka Dejda; Przemyslaw Sapieha; Bruno Larrivée; Isabelle Royal (Angiogenesis, 2020)

Stabilization of myeloid-derived HIFs promotes vascular regeneration in retinal ischemia - Pilar Villacampa; Sidath E. Liyanage; Izabela P. Klaska; Enrico Cristante; Katja E. Menger; Robert D. Sampson; Maeve Barlow; Laura Abelleira-Hervas; Yanai Duran; Alexander J. Smith; Robin R. Ali; Ulrich F. O. Luhmann; et al. (Angiogenesis, 2020)
The retinal vasculature is tightly organized in a structure that provides for the high metabolic demand of neurons while minimizing interference with incident light. The adverse impact of retinal vascular insufficiency is mitigated by adaptive vascular regeneration but exacerbated by pathological neovascularization. Aberrant growth of neovessels in the retina is responsible for impairment of sight in common blinding disorders including retinopathy of prematurity, proliferative diabetic retinopathy, and age-related macular degeneration. Myeloid cells are key players in this process, with diverse roles that can either promote or protect against ocular neovascularization. We have previously demonstrated that myeloid-derived VEGF, HIF1, and HIF2 are not essential for pathological retinal neovascularization. Here, however, we show by cell-specific depletion of Vhl in a mouse model of retinal ischemia (oxygen-induced retinopathy, OIR) that myeloid-derived HIFs promote VEGF and bFGF expression and enhance vascular regeneration in association with improved density and organization of the astrocytic network.

Glucose withdrawal induces Endothelin 1 release with significant angiogenic effect from first trimester (FTM), but not term human umbilical cord perivascular cells (HUCPVC) - Peter Szaraz; Poonam Mander; Nadav Gasner; Max Librach; Farwah Iqbal; Clifford Librach (Angiogenesis, 2020)

Vessel co-option and resistance to anti-angiogenic therapy - Elizabeth A. Kuczynski; Andrew R. Reynolds (Angiogenesis, 2020)

Introduction to special issue: vascular co-option in cancer - Andrew C. Dudley (Angiogenesis, 2020)

Angiotropism, pericytic mimicry and extravascular migratory metastasis: an embryogenesis-derived program of tumor spread - Claire Lugassy; Hynda K. Kleinman; Peter B. Vermeulen; Raymond L. Barnhill (Angiogenesis, 2020)

Vascular co-option in brain metastasis - Pedro García-Gómez; Manuel Valiente (Angiogenesis, 2020)

Vessel co-option in glioblastoma: emerging insights and opportunities - Giorgio Seano; Rakesh K. Jain (Angiogenesis, 2020)
Vessel co-option is the movement of cancer cells towards and along the pre-existing vasculature and is an alternative to angiogenesis to gain access to nutrients. Vessel co-option has been shown as a strategy employed by some glioblastoma (GBM) cells to invade further into the brain, leading to one of the greatest challenges in treating GBM. In GBM, vessel co-option may be an intrinsic feature or an acquired mechanism of resistance to anti-angiogenic treatment. Here, we describe the histological features and the dynamics visualized through intravital microscopy of vessel co-option in GBM, as well as the molecular players discovered until now. We also highlight key unanswered questions, as answering these is critical to improve understanding of GBM progression and for developing more effective approaches for GBM treatment.

Pathological features of vessel co-option versus sprouting angiogenesis - Emily Latacz; Elisabetta Caspani; Raymond Barnhill; Claire Lugassy; Cornelis Verhoef; Dirk Grünhagen; Steven Van Laere; Carlos Fernández Moro; Marco Gerling; Marie Dirix; Luc Y. Dirix; Peter B. Vermeulen (Angiogenesis, 2020)

Models and molecular mechanisms of blood vessel co-option by cancer cells - Yu Zhang; Sarah Wang; Andrew C. Dudley (Angiogenesis, 2020)

13th International HHT Scientific Conference (Angiogenesis, 2019)

Oxygen sensing decoded: a Nobel concept in biology - Arjan W. Griffioen; Joyce Bischoff (Angiogenesis, 2019)

The tumor vasculature an attractive CAR T cell target in solid tumors - Parvin Akbari; Elisabeth J. M. Huijbers; Maria Themeli; Arjan W. Griffioen; Judy R. van Beijnum (Angiogenesis, 2019)
T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now. A number of differences between liquid and solid tumors are likely to cause this discrepancy. The main ones of these are undoubtedly the uncomplicated availability of the target cell within the blood compartment and the abundant expression of the target molecule on the cancerous cells in the case of hematological malignancies. Targets expressed by solid tumor cells are hard to engage due to the non-adhesive and abnormal vasculature, while conditions in the tumor microenvironment can be extremely immunosuppressive. Targets in the tumor vasculature are readily reachable by CAR T cells and reside outside the immunosuppressive tumor microenvironment. It is therefore hypothesized that targeting CAR T cells towards the tumor vasculature of solid tumors may share the excellent effects of CAR T cell therapy with that against hematological malignancies. A few reports have shown promising results. Suggestions are provided for further improvement.

Highlights of the 13th International Hereditary Hemorrhagic Telangiectasia Scientific conference - Hyunwoo Choi; Miles B. Conrad; S. Paul Oh; Beth L. Roman; Andrew J. White (Angiogenesis, 2019)

Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations - Jeremy A. Goss; Dennis J. Konczyk; Patrick J. Smits; Harry P. W. Kozakewich; Ahmad I. Alomari; Alyaa Al-Ibraheemi; Amir H. Taghinia; Belinda H. Dickie; Denise M. Adams; Steven J. Fishman; John B. Mulliken; Matthew L. Warman; et al. (Angiogenesis, 2019)

Revascularization after angiogenesis inhibition favors new sprouting over abandoned vessel reuse - Anthony Mukwaya; Pierfrancesco Mirabelli; Anton Lennikov; Muthukumar Thangavelu; Maria Ntzouni; Lasse Jensen; Beatrice Peebo; Neil Lagali (Angiogenesis, 2019)

Mitochondrial fission protein 1 up-regulation ameliorates senescence-related endothelial dysfunction of human endothelial progenitor cells - Hsueh-Hsiao Wang; Yih-Jer Wu; Ya-Ming Tseng; Cheng-Huang Su; Chin-Ling Hsieh; Hung-I Yeh (Angiogenesis, 2019)