Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis
Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis
复制标题
DOI：
10.1038/s41467-019-10359-x
复制
发表时间：
2019-05-28
影响因子：
16.6
通讯作者：
Eichmann, Anne
中科院分区：
文献类型：
--
作者：
Genet, Gael;Boye, Kevin;Eichmann, Anne
内皮细胞迁移、增殖和存活由VEGF-A激活VEGFR 2触发。然而，这些细胞行为是如何单独调节的仍然是未知的。在这里，我们确定Endophilin-A2（ENDOA 2），一个BAR结构域蛋白，协调网格蛋白独立的内化，作为内皮细胞迁移和萌芽血管生成的关键介质。我们发现，EndoA 2基因敲除小鼠表现出出生后血管生成缺陷和受损的前-后极化的萌芽尖端细胞。ENDOA 2缺陷减少VEGFR 2内化并抑制信号传导效应物PAK而非ERK的下游活化，从而影响前后极性和迁移，但不影响增殖或存活。在机制上，VEGFR 2通过SLIT 2-ROBO途径经由ENDOA 2和ROBO 1的SLIT-ROBO-GAP 1桥接而导向ENDOA 2介导的内吞作用。阻断ENDOA 2介导的内皮细胞迁移减弱氧诱导视网膜病变模型中的病理性血管生成这项工作确定了一个特定的内吞途径，控制一个子集的VEGFR 2介导的反应，可以有针对性地防止过度萌芽血管生成的病理条件。
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.