A collagen Vα1-derived fragment inhibits FGF-2 induced-angiogenesis by modulating endothelial cells plasticity through its heparin-binding site |
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| Institution: | 1. Institute for Advanced Biosciences, INSERM-UGA U1209, CNRS UMR 5309, Site Santé, Allée des Alpes, 38700, La Tronche, France;2. Institut de Génomique Fonctionnelle de Lyon, ENS de Lyon, UMR CNRS 5242, Université Lyon 1, 46 Allée d''Italie, 69364, Lyon cedex 07, France;3. Laboratoire CRRET Faculté des Sciences et Technologie, Université Paris Est-Créteil-Val de Marne, 61 Avenue du Général de Gaulle, 94010, Créteil Cedex, France;1. Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA 19107, USA;2. Departments of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA;3. Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA;4. Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA;5. Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA;1. School of Life Sciences and Technology, Tongji University, Shanghai, China;2. Yantai RC Biotechnologies, Ltd., Yantai, Shandong, China;3. Tongji University Suzhou Institute, Suzhou, Jiangsu, China;4. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China;1. Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA;2. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA;3. Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA;4. Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA, USA;5. Center for Systems and Computational Biology, Wistar Institute, Philadelphia, PA, USA;6. Departments of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA;7. Biogen Idec Inc., Cambridge, MA, USA;8. Flow Cytometry Core Facility, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA;9. Cancer Genomics and Bioinformatics Laboratory, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA;10. Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA;11. Immunology, Microenvironment and Metastasis Program, Wistar Institute, Philadelphia, PA, USA |
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| Abstract: | Type V collagen (ColV) is a component of the endothelial basement membrane zone. During angiogenesis, extracellular matrix remodelling results in the release of active protein fragments that display pro- or anti-angiogenic properties. The latter often exert their activity through their heparin-binding site. We previously characterized a ColVα1-derived fragment called HEPV that contains a high affinity-binding site for heparin and heparan sulphate chains. Here we show that HEPV binds to FGF2 through its heparin-binding site. Using in vitro and in vivo angiogenesis assays, we show that HEPV but not the HEPV mutant at the heparin-binding site, inhibits FGF2-dependant angiogenesis. On the opposite, HEPV does not bind to VEGFA and has no effect on VEGFA-mediated angiogenesis. In 3D collagen gels, the addition of HEPV abrogates endothelial cell invasion and sprouting induced by FGF2. Interestingly, in vivo experiments reveal that HEPV anti-angiogenic activity is associated with the appearance of endothelial to mesenchymal transition (EndMT) markers. Together, these findings indicate that the ColVα1-derived fragment HEPV functions as an anti-angiogenic factor that represses FGF2-mediated angiogenesis through the regulation of endothelial cell plasticity. Previous observations showing that ColV overexpression negatively regulates pathological angiogenesis were left unexplained. Our data provide insights into the possible molecular mechanisms. |
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