Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Dev Cell. 2011 Apr 19;20(4):526-39. doi: 10.1016/j.devcel.2011.02.010. Epub 2011 Mar 10.
Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs). However, the mechanisms underlying vascular "tubulogenesis" are only beginning to be unraveled. We show that endothelial tubulogenesis requires the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAP Arhgap29. Mice lacking Rasip1 fail to form patent lumens in all blood vessels, including the early endocardial tube. Rasipl null angioblasts fail to properly localize the polarity determinant Par3 and display defective cell polarity, resulting in mislocalized junctional complexes and loss of adhesion to extracellular matrix (ECM). Similarly, depletion of either Rasip1 or Arhgap29 in cultured ECs blocks in vitro lumen formation, fundamentally alters the cytoskeleton, and reduces integrin-dependent adhesion to ECM. These defects result from increased RhoA/ROCK/myosin II activity and blockade of Cdc42 and Rac1 signaling. This study identifies Rasip1 as a unique, endothelial-specific regulator of Rho GTPase signaling, which is essential for blood vessel morphogenesis.
心血管功能取决于内皮细胞（ECs）形成有功能的血管。然而，血管“小管形成”的机制才刚刚开始被揭示。我们发现内皮小管形成需要 Ras 相互作用蛋白 1（Rasip1）及其结合伴侣 RhoGAP Arhgap29。缺乏 Rasip1 的小鼠所有血管，包括早期心内膜管，均无法形成有功能的管腔。Rasipl 缺失的血管母细胞无法正确定位极性决定因子 Par3，并表现出细胞极性缺陷，导致连接复合体定位错误和细胞与细胞外基质（ECM）的黏附丧失。同样，在培养的 ECs 中耗尽 Rasip1 或 Arhgap29 均会阻断体外管腔形成，从根本上改变细胞骨架，并减少整合素依赖的 ECM 黏附。这些缺陷是由于 RhoA/ROCK/肌球蛋白 II 活性增加和 Cdc42 和 Rac1 信号通路阻断所致。本研究鉴定出 Rasip1 是一种独特的内皮细胞特异性 Rho GTPase 信号调节因子，对于血管形态发生至关重要。
