p190 RhoGTPase-Activating Protein Links the β1 Integrin/Caveolin-1 Mechanosignaling Complex to RhoA and Actin Remodeling

Abstract

Objective— To determine whether the β1 integrin/caveolin-1 signaling complex plays a role in shear stress regulation of RhoA activity . Methods and Results— Hemodynamic shear stress influences the phenotype of the endothelium. Integrins and RhoA are essential components in the process that allows endothelial cells to adapt to flow. However, the signaling mechanisms that relay from integrins to RhoA are not well defined. Bovine aortic endothelial cells were subjected to laminar shear stress (10 dyne/cm 2 ) for up to 6 hours. β1 integrin blockade inhibited Src family kinases and p190RhoGAP tyrosine phosphorylation observed after the immediate onset of shear stress. Depletion of caveolin-1 blocked the decline in p190RhoGAP tyrosine phosphorylation observed at later points by sustaining Src family kinase activity. The manipulation of β1 integrin and caveolin-1 also altered shear regulation of RhoA activity. More importantly, cells depleted of p190RhoGAP showed faulty temporal regulation of RhoA activity. Each of these treatments attenuated actin reorganization induced by flow. Similarly, stress fibers failed to form in endothelial cells exposed to enhanced blood flow in caveolin-1 knockout mice. Conclusion— Our studies demonstrate that p190RhoGAP links integrins and caveolin-1/caveolae to RhoA in a mechanotransduction cascade that participates in endothelial adaptation to flow.