Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis
In: ISSN: 2041-1723, 2019
Online
academicJournal
Zugriff:
International audience ; 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.
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Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis
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Autor/in / Beteiligte Person: | Genet, Gaël ; Boyé, Kevin ; Mathivet, Thomas ; Ola, Roxana ; Zhang, Feng ; Dubrac, Alexandre ; Li, Jinyu ; Genet, Nafiisha ; Henrique Geraldo, Luiz ; Benedetti, Lorena ; Künzel, Steffen ; Pibouin-Fragner, Laurence ; Thomas, Jean-Leon ; Eichmann, Anne ; Yale School of Medicine New Haven, Connecticut (YSM) ; Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970) ; 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Institut du Cerveau = Paris Brain Institute (ICM) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Sorbonne Université (SU) ; CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) |
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Zeitschrift: | ISSN: 2041-1723, 2019 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2019 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41467-019-10359-x |
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