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. © 2011 Siddiqui et al.
CITATION STYLE
Rizwan Siddiqui, M., Komarova, Y. A., Vogel, S. M., Gao, X., Bonini, M. G., Rajasingh, J., … Malik, A. B. (2011). Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability. Journal of Cell Biology, 193(5), 841–850. https://doi.org/10.1083/jcb.201012129
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