Abstract 14029: Deletion of Rac1 in Smooth Muscle Cells Induces Hypertension in Mice by Depressing the Nitric Oxide-Dependent Signaling Pathway
The Rho family proteins (RhoA, Rac1, Cdc42) are defined as central regulators of smooth muscle cells (SMC) functions. To determine in vivo the role of Rac1 in the vascular system, we generated a conditional model of Rac1 gene inactivation in SMC (SM-Rac1-KO). SM-Rac1-KO mice display high systolic blood pressure (137±2 mmHg vs 125±3 mmHg in control mice; n≥7, p<0.05). The analysis of the contractile properties of aorta and mesenteric arteries shows no modification of the myogenic tone and minor changes in responses to vasoconstrictors in SM-Rac1-KO compared to control mice. In contrast, the nitric oxide (NO)-dependent vasorelaxation is attenuated by 14±3% (n=8, p<0.01) in aorta, and by 45±5% (n=12, p<0.01) in mesenteric arteries of SM-Rac1-KO mice. Isoproterenol- and EDHF-induced relaxations are not modified suggesting a specific alteration of the signaling pathway downstream of the NO in SM-Rac1-KO mice. This hypothesis is supported by the resistance of SM-Rac1-KO mice to the inhibition of the NO signaling pathway (L-NAME 300 mg/kg/day) while this treatment induces a rise in control mice blood pressure (19±1 mmHg, n=7). Although Western-blot analyses did not reveal any change in the expression of the main regulatory elements involved in the NO pathway (eNOS, cGK, PDE5), cGMP level is decreased by 50% in the aorta from SM-Rac1-KO mice compared to controls, due to the loss of Rac1/Pak1-mediated down-regulation of type 5 phosphodiesterase activity in SM-Rac1-KO mice. This change is associated with an overactivation of RhoA/Rho-kinase signaling. We identified the myosin phosphatase-RhoA interacting protein, p116RIP3, as a molecular link between Rac1and RhoA. The loss of Rac1 expression in SMC prevents NO-mediated p116RIP3/RhoA interaction and the subsequent inhibition of RhoA/Rho kinase signaling. These data suggest for the first time an in vivo role of Rac1 in vascular tone and arterial blood pressure regulation. Rac1 deletion in SMC induces hypertension in mice through alteration of NO/cGMP signaling and decreased NO-induced p116RIP3/RhoA interaction, RhoA inhibition and relaxation.
- © 2012 by American Heart Association, Inc.