Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization.
Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization.
复制标题
靶向NCK介导的内皮细胞前射线极性会抑制新血管形成。
DOI：
10.1161/circulationaha.115.017537
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发表时间：
2016-01-26
期刊：
影响因子：
37.8
通讯作者：
Eichmann A
中科院分区：
文献类型：
--
作者：
Dubrac A;Genet G;Ola R;Zhang F;Pibouin-Fragner L;Han J;Zhang J;Thomas JL;Chedotal A;Schwartz MA;Eichmann A
萌芽血管生成是驱动缺血组织中血管生长的关键过程，并且是许多疾病（包括湿性黄斑变性和伤口愈合）中的重要药物靶标。形成芽的内皮细胞必须发展前后极性以允许芽延伸。衔接蛋白Nck 1和2是已知的细胞骨架动力学和极性的调节剂，但它们在血管生成中的功能知之甚少。在这里，我们表明，NCK衔接子所需的内皮细胞前后极性和迁移的血管生成生长因子VEGF-A和Slit 2的下游。携带可诱导的内皮特异性Nck 1/2缺失的小鼠不能发展前后极化血管芽，并在出生后视网膜和胚胎发育期间表现出严重的血管生成缺陷。NCK 1和2的失活通过阻止VEGF-A和Slit 2激活Cdc 42和Pak 2来抑制极性。从机制上讲，NCK与ROBO 1的结合是Slit 2和VEGF诱导的前后极性所必需的。通过靶向Nck 1/2选择性抑制极化内皮细胞迁移，防止Notch或Bmp信号传导抑制诱导的超出芽，以及病理性眼部新血管形成和伤口愈合。这些数据揭示了一种新的信号整合机制，涉及NCK 1/2，ROBO 1/2和VEGFR 2，控制内皮细胞的前-后极性在萌芽血管生成。
Sprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2. Mice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2 and VEGF induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, as well as pathological ocular neovascularization and wound healing. These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2 and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis.