0176 : Smooth muscle specific Rac1 deficiency induces hypertension by over activation of RhoA/Rho-kinase signaling pathway

The small GTPase RhoA and its target, Rho kinase, play essential role in both blood pressure regulation and vascular smooth muscle contraction. Increasing evidence implicates over activation of this signaling pathway as a critical event in the pathogenesis of hypertension. Interestingly, it has been recently described that Rac1 could antagonize RhoA-dependent functions. However, the role of Rac1 in the regulation of vascular tone and blood pressure is not fully elucidated. Here we assessed the hypothesis that smooth muscle Rac1 participates in the control of blood pressure. To define the role of vascular smooth muscle cells (vSMC) Rac1 in vivo in the control of blood pressure, we generated inducible, smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and analyzed cardiovascular parameters. Following induction of Rac1 deletion, SM-Rac1-KO mice rapidly develop high systolic blood pressure (+15±2 mmHg, n=19, p=0.02). Treatment with the Rho kinase inhibitor fasudil decreases systolic arterial pressure to a level similar in control and SM-Rac1-KO mice suggesting that RhoA/Rho kinase signaling is involved in the rise in systolic blood pressure induced by SM-Rac1 deletion. This is confirmed by immunoblot analysis in aorta that reveals an increase of activated RhoA (348± 19% of control, n=4, p<0.05) and Rho-kinase activity (390±25% of control, n=4, p