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首页> 外文期刊>American Journal of Physiology >VE-cadherin-p120 interaction is required for maintenance of endothelial barrier function.
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VE-cadherin-p120 interaction is required for maintenance of endothelial barrier function.

机译：VE-钙粘着蛋白-p120相互作用是维持内皮屏障功能所必需的。

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摘要

Interaction of p120 with juxtamembrane domain (JMD) of VE-cadherin has been implicated in regulation of endothelial cell-cell adhesion. We used a number of approaches to alter the level of p120 available for binding to VE-cadherin as a means to investigate the role of p120-VE-cadherin interaction in regulation of barrier function in confluent endothelial monolayers. Expression of an epitope-tagged fragment corresponding to JMD of VE-cadherin resulted in a decrease in endothelial barrier function as assessed by changes in albumin clearance and electrical resistance. Binding of JMD-Flag to p120 resulted in a decreased level of p120. In addition to decreasing p120 level, expression of JMD also decreased level of VE-cadherin. Expression of JMD also caused an increase in MLC phosphorylation and rearrangement of actin cytoskeleton, which, coupled with decreased cadherin, can contribute to loss of barrier function. Reducing p120 by siRNA resulted in a decrease in VE-cadherin, whereas increasing the level of p120 increased the level of VE-cadherin, demonstrating that p120 regulates the level of VE-cadherin. Overexpression of p120 was, however, associated with decreased barrier function and rearrangement of the actin cytoskeleton. Interestingly, expression of p120 was able to inhibit thrombin-induced increases in MLC phosphorylation, suggesting that p120 inhibits activation of Rho/Rho kinase pathway in endothelial cells. Excess p120 also prevented JMD-induced increases in MLC phosphorylation, correlating this phosphorylation with Rho/Rho kinase pathway. These findings show p120 plays a major role in regulating endothelial barrier function, as either a decrease or increase of p120 resulted in disruption of permeability across cell monolayers.
机译：p120与VE-钙黏着蛋白的近膜结构域（JMD）的相互作用已牵涉到内皮细胞-细胞粘附的调节。我们使用了多种方法来改变可用于结合VE-钙黏着蛋白的p120的水平，以此作为研究p120-VE-钙黏着蛋白相互作用在融合内皮单层屏障功能调节中的作用的手段。通过清蛋白清除率和电阻的变化评估，与VE-钙粘蛋白的JMD相对应的表位标记片段的表达导致内皮屏障功能的降低。 JMD-Flag与p120的结合导致p120水平降低。除了降低p120水平，JMD的表达还降低了VE-钙粘蛋白的水平。 JMD的表达还引起MLC磷酸化的增加和肌动蛋白细胞骨架的重排，再加上钙黏着蛋白的减少，可能导致屏障功能的丧失。 siRNA降低p120导致VE-钙黏着蛋白减少，而增加p120的水平则增加VE-钙黏着蛋白的水平，表明p120调节VE-钙黏着蛋白的水平。然而，p120的过表达与屏障功能降低和肌动蛋白细胞骨架重排有关。有趣的是，p120的表达能够抑制凝血酶诱导的MLC磷酸化的增加，表明p120抑制了内皮细胞中Rho / Rho激酶途径的激活。过量的p120还阻止了JMD诱导的MLC磷酸化增加，从而使该磷酸化与Rho / Rho激酶途径相关。这些发现表明，p120在调节内皮屏障功能中起主要作用，因为p120的减少或增加会导致跨细胞单层渗透性的破坏。

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