Faculty Collaboration Database

Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability. J Cell Biol 2011 May 30;193(5):841-50

Date

06/01/2011

Pubmed ID

21624953

Pubmed Central ID

PMC3105546

DOI

10.1083/jcb.201012129

Scopus ID

2-s2.0-79959425204 (requires institutional sign-in at Scopus site)   91 Citations

Abstract

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.

Author List

Siddiqui MR, Komarova YA, Vogel SM, Gao X, Bonini MG, Rajasingh J, Zhao YY, Brovkovych V, Malik AB

MESH terms used to index this publication - Major topics in bold

Animals
Caveolin 1
Cells, Cultured
Endothelial Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide
Nitric Oxide Synthase Type III
Permeability
Peroxynitrous Acid
Signal Transduction
rhoA GTP-Binding Protein