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Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis.
- Source :
-
Nature communications [Nat Commun] 2019 May 28; Vol. 10 (1), pp. 2350. Date of Electronic Publication: 2019 May 28. - Publication Year :
- 2019
-
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.
- Subjects :
- Animals
Cell Movement genetics
Cell Polarity genetics
Cell Proliferation genetics
Cell Survival genetics
Endocytosis genetics
Endothelial Cells cytology
Intercellular Signaling Peptides and Proteins metabolism
MAP Kinase Signaling System
Mice
Mice, Knockout
Nerve Tissue Proteins metabolism
Receptors, Immunologic metabolism
Retinal Vessels cytology
Retinal Vessels growth & development
p21-Activated Kinases metabolism
Roundabout Proteins
Acyltransferases genetics
Endothelial Cells metabolism
Neovascularization, Physiologic genetics
Vascular Endothelial Growth Factor Receptor-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31138815
- Full Text :
- https://doi.org/10.1038/s41467-019-10359-x