Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis.
Nat Commun
; 10(1): 2350, 2019 05 28.
Article
en En
| MEDLINE
| ID: mdl-31138815
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Aciltransferasas
/
Neovascularización Fisiológica
/
Receptor 2 de Factores de Crecimiento Endotelial Vascular
/
Células Endoteliales
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos