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Nat Commun. 2019 May 28;10(1):2350. doi: 10.1038/s41467-019-10359-x.

Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis.

Author information

1
Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
2
Inserm U970, Paris Cardiovascular Research Center, Paris, 75015, France.
3
Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania, Department of Basic, Preventive and Clinical Science, University of Transylvania, Brasov, Romania.
4
Department of Neuroscience and Cell Biology, School of Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
5
Department of Neurology, Yale University School of Medicine, New Haven, CT, 06511, USA.
6
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, Paris, France.
7
Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA. anne.eichmann@yale.edu.
8
Inserm U970, Paris Cardiovascular Research Center, Paris, 75015, France. anne.eichmann@yale.edu.
9
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06511, USA. anne.eichmann@yale.edu.

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.

PMID:
31138815
PMCID:
PMC6538628
DOI:
10.1038/s41467-019-10359-x
[Indexed for MEDLINE]
Free PMC Article

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