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.
Highlights
Endothelial cell migration, proliferation and survival are triggered by Vascular endothelial growth factor A (VEGF)-A activation of VEGF receptor 2 (VEGFR2)
Since tip cell migration is controlled by VEGFR23–7, and ENDOA2 has been implicated in VEGF endocytosis[27], we determined whether ENDOA2 loss of function affected VEGFR2 a Vascular progression (d/D)
Our results identify the SLIT2-ROBO1 guidance pathway as a critical mediator of ENDOA2-mediated VEGFR2 uptake and subsequent polarized endothelial cell migration
Summary
Endothelial cell migration, proliferation and survival are triggered by VEGF-A activation of VEGFR2. How these cell behaviors are regulated individually is still unknown. We identify Endophilin-A2 (ENDOA2), a BAR-domain protein that orchestrates CLATHRINindependent internalization, as a critical mediator of endothelial cell migration and sprouting angiogenesis. 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. VEGF binding to VEGFR2 triggers receptor dimerization and phosphorylation of tyrosine residues in the cytoplasmic kinase domain, in turn activating various intracellular cascades, including PI3K/AKT, MAPK, SRC, and PAK signaling, to mediate survival, proliferation, and migration[7,8,9]. FEME is triggered upon activation of specific receptors by their cognate ligands[29]
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