Enhanced Ca2+-Dependent Activation of Phosphoinositide 3-Kinase Class IIα Isoform-Rho Axis in Blood Vessels of Spontaneously Hypertensive Rats

Rho-mediated inhibition of myosin light chain (MLC) phosphatase (MLCP), together with Ca2+-dependent MLC kinase activation, constitutes the major signaling mechanisms for vascular smooth muscle contraction. We recently unveiled the involvement of Ca2+-induced, phosphoinositide 3-kinase (PI3K) class II alpha isoform (PI3K-C2 alpha)-dependent Rho activation and resultant Rho kinase-dependent MLCP suppression in membrane depolarization- and receptor agonist-induced contraction. It is unknown whether Ca2+ - and PI3K-C2 alpha-dependent regulation of MLCP is altered in vascular smooth muscle of hypertensive animals and is involved in hypertension. Therefore, we studied the role of the Ca2+-PI3K-C2 alpha-Rho-MLCP pathway in spontaneously hypertensive rats (SHRs). PI3K-C2 alpha was readily detected in various vascular beds of Wistar-Kyoto rats and activated by high KCl. High KCl also stimulated vascular Rho activity and phosphorylation of the MLCP regulatory subunit MYPT1 at Thr(853) in a PI3K inhibitor wortmannin-sensitive manner. In mesenteric and other vessels of SHRs at the hypertensive but not the prehypertensive stage, the activity of PI3K-C2 alpha but not class I PI3K p110 alpha was elevated with concomitant rises of Rho activity and Thr(853)-phosphorylation of MYPT1, as compared with normotensive controls. Infusion of the Ca2+ channel antagonist nicardipine reduced blood pressure with suppression of vascular activity of PI3K-C2 alpha-Rho and phosphorylation of MYPT1 in hypertensive SHRs. Infusion of wortmannin lowered blood pressure with inhibition of PI3K-C2 alpha-Rho activities and MYPT1 phosphorylation in hypertensive SHRs. These observations suggest that an increased activity of the Ca2+-PI3K-C2 alpha-Rho signaling pathway with resultant augmented MLCP suppression contributes to hypertension in SHRs. The Ca2+- and PI3K-C2 alpha-dependent Rho stimulation in vascular smooth muscle may be a novel, promising target for treating hypertension. (Hypertension. 2010;56:934-941.)