S-Nitrosylation of β-Catenin by eNOS-Derived NO Promotes VEGF-Induced Endothelial Cell Permeability

SummaryDisruption of adherens junctions between endothelial cells results in compromised endothelial barrier function and in altered angiogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is essential for increased vascular permeability induced by vascular endothelial growth factor (VEGF). However, the molecular mechanisms by which NO modulates endothelial permeability remain elusive. Here, we show that, within adherens junctions, β-catenin is a substrate for S-nitrosylation by NO. Stimulation of endothelial cells with VEGF induces S-nitrosylation of β-catenin, which is dependent on expression and activity of eNOS. Furthermore, VEGF-induced S-nitrosylation of β-catenin is inhibited in eNOS−/− mice. We identify Cys619, located within the VE-cadherin interaction site, as the major S-nitrosylation locus in response to VEGF. Inhibition of S-nitrosylation at Cys619 prevents NO-dependent dissociation of β-catenin from VE-cadherin and disassembly of adherens junction complexes and inhibits VEGF-stimulated endothelial permeability. Thus, we identify S-nitrosylation of β-catenin as a modulator of intercellular contacts between endothelial cells.

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► β- catenin is a substrate for S-nitrosylation by NO in endothelial cells
► VEGF stimulation induces eNOS-dependent S-nitrosylation of β-catenin
► S-nitrosylation of Cys619 of β-catenin promotes dissociation from VE-cadherin
► S-nitrosylation of Cys619 is essential for VEGF-induced endothelial permeability