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

Abstract

The adherens junction complex, composed mainly of vascular endothelial (VE)-cadherin, β-catenin, p120, and γ-catenin, is the main element of the endothelial barrier in postcapillary venules.S-nitrosylation of β-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 β-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.

Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability

“…Basal production of NO controls vascular tone and vasorelaxation in response to increased blood flow, whereas hyper-activation of eNOS in response to VEGF or pro-inflammatory stimuli such as Platelet-Activating factor (PAF) triggers S-nitrosylation of VE-cadherin, β-catenin, and p120 catenin 213–215 . S-nitrosylation, the covalent attachment of S-nitrosothiol to a cysteine thiol 216 , represents another regulatory pathway of AJ stability.…”

“…S-nitrosylation, the covalent attachment of S-nitrosothiol to a cysteine thiol 216 , represents another regulatory pathway of AJ stability. Similar to phosphorylation, S-nitrosylation reversibly modulates affinity of β- and p120- catenin proteins to VE-cadherin 213–215, 217 . S-nitrosylation of β-catenin on the Cys619 residue promotes dissociation of β-catenin from VE-cadherin causing destabilization of AJs and resultant hyper-permeability of the endothelial barrier 213–215, 217 .…”

“…Similar to phosphorylation, S-nitrosylation reversibly modulates affinity of β- and p120- catenin proteins to VE-cadherin 213–215, 217 . S-nitrosylation of β-catenin on the Cys619 residue promotes dissociation of β-catenin from VE-cadherin causing destabilization of AJs and resultant hyper-permeability of the endothelial barrier 213–215, 217 . Deletion of eNOS causes a blunted VEGF-mediated permeability response 217 , further supporting the role of NO redox signaling in regulating endothelial barrier function.…”

New Member of Endothelial Arsenal Against Inflammation

“…Proteins involved in regulatory functions include intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule- 1 (VCAM-1), and vascular endothelial cadherin (VE-cadherin). ICAM-1 and VCAM-1 play an important role in adhesion and migration of leukocytes in inflammation 7 , while VE-cadherin participates in the regulation of microvascular transport 8, 9 .…”

“…Importantly, an endogenous function (in regards to endothelium) of eNOS-derived NO is to serve as a fundamental signal for the onset of hyperpermeability in response to inflammatory agents, a function implemented mainly via Snitrosylation, i.e., binding of NO. to cysteine 9, 16, 17 . Prostacyclin, endothelin, carbon monoxide and endothelial hyperpolarizing factor share with NO the vascular function of controlling blood flow.…”