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Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis

Author

Listed:
  • 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
    University of Transylvania)

  • 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
    Yale University School of Medicine
    Sorbonne Universités, UPMC Université Paris 06, Institut National de la Santé et de la Recherche Médicale U1127, Centre National de la Recherche Scientifique, AP-HP, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière)

  • Anne Eichmann

    (Yale University School of Medicine
    Inserm U970, Paris Cardiovascular Research Center
    Yale University School of Medicine)

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.

Suggested Citation

  • 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-Fragne, 2019. "Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10359-x
    DOI: 10.1038/s41467-019-10359-x
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    Cited by:

    1. Tomasz J. Nawara & Yancey D. Williams & Tejeshwar C. Rao & Yuesong Hu & Elizabeth Sztul & Khalid Salaita & Alexa L. Mattheyses, 2022. "Imaging vesicle formation dynamics supports the flexible model of clathrin-mediated endocytosis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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