Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis
| Autor: | Gael Genet, Laurence Pibouin-Fragner, Thomas Mathivet, Kevin Boyé, Steffen E. Künzel, Anne Eichmann, Roxana Ola, Jean-Leon Thomas, Feng Zhang, Jinyu Li, Luiz Henrique Medeiros Geraldo, Alexandre Dubrac, Lorena Benedetti, Nafiisha Genet |
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| Přispěvatelé: | Yale University School of Medicine, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP] |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Angiogenesis [SDV]Life Sciences [q-bio] Endocytic cycle General Physics and Astronomy 02 engineering and technology Neovascularization Mice Cell Movement Receptors Immunologic lcsh:Science Internalization media_common Mice Knockout Multidisciplinary Chemistry Cell Polarity respiratory system 021001 nanoscience & nanotechnology Endocytosis 3. Good health Cell biology Endothelial stem cell cardiovascular system Intercellular Signaling Peptides and Proteins medicine.symptom 0210 nano-technology circulatory and respiratory physiology Cell Survival MAP Kinase Signaling System Science media_common.quotation_subject Neovascularization Physiologic Nerve Tissue Proteins Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system medicine Animals Cell Proliferation Sprouting angiogenesis Growth factor signalling Endothelial Cells Retinal Vessels General Chemistry Vascular Endothelial Growth Factor Receptor-2 030104 developmental biology p21-Activated Kinases lcsh:Q Acyltransferases |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications, Nature Publishing Group, 2019, 10 (1), ⟨10.1038/s41467-019-10359-x⟩ |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-10359-x |
| Popis: | Endothelial cell migration, proliferation and survival are triggered by VEGF-A activation of VEGFR2. However, how these cell behaviors are regulated individually is still unknown. Here we identify Endophilin-A2 (ENDOA2), a BAR-domain protein that orchestrates CLATHRIN-independent internalization, as a critical mediator of endothelial cell migration and sprouting angiogenesis. We show that EndoA2 knockout mice exhibit postnatal angiogenesis defects and impaired front-rear polarization of sprouting tip cells. ENDOA2 deficiency reduces VEGFR2 internalization and inhibits downstream activation of the signaling effector PAK but not ERK, thereby affecting front-rear polarity and migration but not proliferation or survival. Mechanistically, VEGFR2 is directed towards ENDOA2-mediated endocytosis by the SLIT2-ROBO pathway via SLIT-ROBO-GAP1 bridging of ENDOA2 and ROBO1. Blocking ENDOA2-mediated endothelial cell migration attenuates pathological angiogenesis in oxygen-induced retinopathy models. This work identifies a specific endocytic pathway controlling a subset of VEGFR2 mediated responses that could be targeted to prevent excessive sprouting angiogenesis in pathological conditions. VEGF-A/VEGFR2 signaling is a key driver of endothelial cell migration during sprouting angiogenesis. Here Genet et al. show that endophilin A2 regulates these processes by mediating clathrin-independent VEGFR2 internalization. |
| Databáze: | OpenAIRE |
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