S-nitrosylation regulates VE-cadherin phosphorylation and internalization in microvascular permeability.

ABSTRACT

The adherens junction complex, composed mainly of vascular endothelial (VE)-cadherin, ß-catenin, p120, and γ-catenin, is the main element of the endothelial barrier in postcapillary venules.S-nitrosylation of ß-catenin and p120 is an important step in proinflammatory agents-induced hyperpermeability. We investigated in vitro and in vivo whether or not VE-cadherin isS-nitrosylated using platelet-activating factor (PAF) as agonist. We report that PAF-stimulates S-nitrosylation of VE-cadherin, which disrupts its association with ß-catenin. In addition, based on inhibition of nitric oxide production, our results strongly suggest that S-nitrosylation is required for VE-cadherin phosphorylation on tyrosine and for its internalization. Our results unveil an important mechanism to regulate phosphorylation of junctional proteins in association with S-nitrosylation.