VE-Cadherin-Mediated Cell-Cell Interaction Suppresses Sprouting via Signaling to MLC2 Phosphorylation
VE-Cadherin-Mediated Cell-Cell Interaction Suppresses Sprouting via Signaling to MLC2 Phosphorylation
复制标题
DOI：
10.1016/j.cub.2009.02.057
复制
发表时间：
2009-04-28
期刊：
影响因子：
9.2
通讯作者：
Mavria, Georgia
中科院分区：
文献类型：
--
作者：
Abraham, Sabu;Yeo, Margaret;Mavria, Georgia
在新血管形成过程中，血管生成芽的停止对于功能性脉管系统的形成是必要的。芽是如何停止的尚不清楚，但它与稳定的细胞间连接的形成是同时发生的[1]。我们报道，血管内皮钙黏蛋白（VE - cadherin），它负责内皮黏附连接的组织[2,3]，在芽的停止过程中起着关键作用。在器官型血管生成实验和斑马鱼胚胎中破坏血管内皮钙黏蛋白的功能会刺激芽的生成。我们表明血管内皮钙黏蛋白向依赖于Rho激酶的肌球蛋白轻链2磷酸化发出信号，导致肌动球蛋白收缩[4]，这调节了血管内皮钙黏蛋白在细胞 - 细胞连接处的分布。血管内皮钙黏蛋白拮抗血管内皮生长因子受体2（VEGFR2）信号，因此，抑制血管内皮钙黏蛋白、Rho激酶或肌动球蛋白收缩会导致由血管内皮生长因子驱动的、依赖于Rac1的芽生成。这些发现表明了一种新的机制，即细胞 - 细胞黏附通过增加细胞连接处的肌动球蛋白收缩来抑制依赖于Rac1的迁移和芽生成。
During new blood vessel formation, the cessation of angiogenic sprouting is necessary for the generation of functional vasculature. How sprouting is halted is not known, but it is contemporaneous with the development of stable intercellular junctions [1]. We report that VE-cadherin, which is responsible for endothelial adherens junction organization [2, 3], plays a crucial role in the cessation of sprouting. Abrogating VE-cadherin function in an organotypic angiogenesis assay and in zebrafish embryos stimulates sprouting. We show that VE-cadherin signals to Rho-kinase-dependent myosin light-chain 2 phosphorylation, leading to actomyosin contractility [4], which regulates the distribution of VE-cadherin at cell-cell junctions. VE-cadherin antagonizes VEGFR2 signaling, and consequently, inhibition of VE-cadherin, Rho-kinase, or actomyosin contractility leads to VEGF-driven, Rac1-dependent sprouting. These findings suggest a novel mechanism by which cell-cell adhesion suppresses Rac1-dependent migration and sprouting by increasing actomyosin contractility at cell junctions.