Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis

Gael Genet, Kevin Boyé, Thomas Mathivet, Roxana Ola, Feng Zhang, Alexandre Dubrac, Jinyu Li, Nafiisha Genet, Luiz Henrique Geraldo, Lorena Benedetti, Steffen Künzel, Laurence Pibouin-Fragner, Jean-Leon Thomas and Anne Eichmann ()
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Gael Genet: Yale University School of Medicine
Kevin Boyé: Yale University School of Medicine
Thomas Mathivet: Inserm U970, Paris Cardiovascular Research Center
Roxana Ola: Yale University School of Medicine
Feng Zhang: Yale University School of Medicine
Alexandre Dubrac: Yale University School of Medicine
Jinyu Li: Yale University School of Medicine
Nafiisha Genet: Yale University School of Medicine
Luiz Henrique Geraldo: Inserm U970, Paris Cardiovascular Research Center
Lorena Benedetti: Yale University School of Medicine
Steffen Künzel: Yale University School of Medicine
Laurence Pibouin-Fragner: Inserm U970, Paris Cardiovascular Research Center
Jean-Leon Thomas: Yale University School of Medicine
Anne Eichmann: Yale University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10359-x

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