Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5

G protein–mediated signaling plays a decisive role in blood pressure regulation and the phenotype of vascular smooth muscle cells (VSMCs); however, the relevance of proteins that restrict G protein activity is not well characterized in this context. Here, we investigated the influence of regulator of G protein signaling 5 (RGS5), an inhibitor of Gαq/11 and Gαi/o activity, on blood pressure and the VSMC phenotype during experimental hypertension. In mice, loss of RGS5 did not affect baseline blood pressure, but prevented hypertension-induced structural remodeling. RGS5-deficient arterial VSMCs did not acquire a synthetic phenotype as evidenced by their inability to decrease the abundance of contractile markers—α-smooth muscle actin and smooth muscle–myosin heavy chain—or to proliferate under these conditions. Mechanistically, hypertensive pressure levels or biomechanical stretch are sufficient to increase the expression of RGS5. Loss of RGS5 severely impairs the activation of RhoA and stress fiber formatio...