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1 Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, USA
2 Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV, USA
* To whom correspondence should be addressed. E-mail: vincenp{at}mail.amc.edu.
The interaction of p120 with the juxtamembrane domain (JMD) of VE-cadherin has been implicated in the 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 the regulation of barrier function in confluent endothelial monolayers. Expression of an epitope-tagged fragment corresponding to the JMD of VE-cadherin resulted in a decrease in endothelial barrier function as assessed by changes in albumin clearance and electrical resistance. Binding of JMDFlag to p120 resulted in a decrease in the level of p120. In addition to decreasing p120 level, expression of JMD also resulted in a decrease in the level of VE-cadherin. The expression of JMD also caused an increase in MLC phosphorylation and rearrangement of the actin cytoskeleton, which coupled with the decrease in cadherin, can contribute to a 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. The over-expression of p120 was, however, associated with a decrease in 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 the Rho/Rho Kinase pathway in endothelial cells. Excess p120 also prevented JMD-induced increases in MLC phosphorylation correlating this phosphorylation with the Rho/Rho Kinase pathway. These findings show that p120 plays a major role in regulating endothelial barrier function, as either a decrease or increase of p120 resulted in the disruption of permeability across the cell monolayers.
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