Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis

• Published in: Nature communications Vol. 10; no. 1; pp. 2350 - 15
• Main Authors: Genet, Gael, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/89; 14; 14/63; 631/136/16; 631/80/313/1461; 631/80/86/2368; 96; 96/106; 96/95; Activation; Acyltransferases - genetics; Angiogenesis; Animals; Cardiology and cardiovascular system; Cell adhesion & migration; Cell migration; Cell Movement - genetics; Cell Polarity - genetics; Cell Proliferation - genetics; Cell survival; Cell Survival - genetics; Clathrin; Endocytosis; Endocytosis - genetics; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Human health and pathology; Humanities and Social Sciences; Intercellular Signaling Peptides and Proteins - metabolism; Internalization; Life Sciences; MAP Kinase Signaling System; Mice; Mice, Knockout; multidisciplinary; Neovascularization, Physiologic - genetics; Nerve Tissue Proteins - metabolism; p21-Activated Kinases - metabolism; Polarity; Receptors, Immunologic - metabolism; Retinal Vessels - cytology; Retinal Vessels - growth & development; Retinopathy; Robo protein; Roundabout Proteins; Science; Science (multidisciplinary); Slit protein; Survival; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10359-x

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.