Caveolin-1–eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability

MR Siddiqui, YA Komarova, SM Vogel, X Gao… - Journal of Cell …, 2011 - rupress.org
MR Siddiqui, YA Komarova, SM Vogel, X Gao, MG Bonini, J Rajasingh, YY Zhao…
Journal of Cell Biology, 2011rupress.org
Endothelial barrier function is regulated by adherens junctions (AJs) and caveolae-mediated
transcellular pathways. The opening of AJs that is observed in caveolin-1−/−(Cav-1−/−)
endothelium suggests that Cav-1 is necessary for AJ assembly or maintenance. Here, using
endothelial cells isolated from Cav-1−/− mice, we show that Cav-1 deficiency induced the
activation of endothelial nitric oxide synthase (eNOS) and the generation of nitric oxide (NO)
and peroxynitrite. We assessed S-nitrosylation and nitration of AJ-associated proteins to …
Endothelial barrier function is regulated by adherens junctions (AJs) and caveolae-mediated transcellular pathways. The opening of AJs that is observed in caveolin-1−/− (Cav-1−/−) endothelium suggests that Cav-1 is necessary for AJ assembly or maintenance. Here, using endothelial cells isolated from Cav-1−/− mice, we show that Cav-1 deficiency induced the activation of endothelial nitric oxide synthase (eNOS) and the generation of nitric oxide (NO) and peroxynitrite. We assessed S-nitrosylation and nitration of AJ-associated proteins to identify downstream NO redox signaling targets. We found that the GTPase-activating protein (GAP) p190RhoGAP-A was selectively nitrated at Tyr1105, resulting in impaired GAP activity and RhoA activation. Inhibition of eNOS or RhoA restored AJ integrity and diminished endothelial hyperpermeability in Cav-1−/− mice. Thrombin, a mediator of increased endothelial permeability, also induced nitration of p120-catenin–associated p190RhoGAP-A. Thus, eNOS-dependent nitration of p190RhoGAP-A represents a crucial mechanism for AJ disassembly and resultant increased endothelial permeability.
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