Local VE-cadherin mechanotransduction triggers long-ranged remodeling of endothelial monolayers
Local VE-cadherin mechanotransduction triggers long-ranged remodeling of endothelial monolayers
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DOI：
10.1242/jcs.159954
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发表时间：
2015-04-01
影响因子：
4
通讯作者：
Leckband, Deborah E.
中科院分区：
文献类型：
--
作者：
Barry, Adrienne K.;Wang, Ning;Leckband, Deborah E.
在这项研究中，我们提出的结果表明，机械转导血管内皮钙粘蛋白（VE-钙粘蛋白，也被称为CDH 5）复合物在内皮细胞触发局部细胞骨架重塑，也激活全球信号，改变外周细胞间连接和破坏细胞接触远离力的应用程序的网站。先前的研究已经记录了肌动球蛋白收缩力对粘附连接重塑的影响，但VE-钙粘蛋白在力觉中的作用及其影响内皮细胞和组织力学的能力尚未得到证实。使用机械操作VE-钙粘蛋白债券和共聚焦成像，我们证明VE-钙粘蛋白为基础的机械转导。然后，我们证明，它需要嗜同性VE-钙粘蛋白连接，一个完整的肌动球蛋白细胞骨架，Rho相关蛋白激酶1（ROCK 1）和磷酸肌醇3-激酶。VE-钙粘蛋白介导的机械转导触发了局部肌动蛋白和黏着斑蛋白的募集，以及改变局灶性粘连和破坏外周细胞间连接的全局信号。共聚焦成像显示，VE-钙粘蛋白特异性变化似乎跨越细胞连接传播，破坏远端内皮间连接。这些结果表明VE-钙粘蛋白粘附和肌动球蛋白细胞骨架在一个综合的，机械敏感的网络，既诱导局部细胞骨架重塑的网站上的力的应用和调节内皮组织的整体完整性的核心作用。
In this study, we present results demonstrating that mechanotransduction by vascular endothelial cadherin (VE-cadherin, also known as CDH5) complexes in endothelial cells triggers local cytoskeletal remodeling, and also activates global signals that alter peripheral intercellular junctions and disrupt cell-cell contacts far from the site of force application. Prior studies have documented the impact of actomyosin contractile forces on adherens junction remodeling, but the role of VE-cadherin in force sensation and its ability to influence endothelial cell and tissue mechanics globally have not been demonstrated. Using mechanical manipulation of VE-cadherin bonds and confocal imaging, we demonstrate VE-cadherinbased mechanotransduction. We then demonstrate that it requires homophilic VE-cadherin ligation, an intact actomyosin cytoskeleton, Rho-associated protein kinase 1 (ROCK1) and phosphoinositide 3-kinase. VE-cadherin-mediated mechanotransduction triggered local actin and vinculin recruitment, as well as global signals that altered focal adhesions and disrupted peripheral intercellular junctions. Confocal imaging revealed that VE-cadherin-specific changes appear to propagate across cell junctions to disrupt distant interendothelial junctions. These results demonstrate the central role of VE-cadherin adhesions and the actomyosin cytoskeleton within an integrated, mechanosensitive network that both induces local cytoskeletal remodeling at the site of force application and regulates the global integrity of endothelial tissues.