Hypertension Mechanisms: RGS2 Coordinates Gq/11 and Gi Signaling in Endothelium and Smooth Muscle of the Resistance Vasculature

RGS2 attenuates signaling by Gq/11α which mediate the action of many vasoactive substances, Gi/oα and adenylyl cyclases. RGS2 is expressed in tissues involved in blood pressure (BP) control and is induced by angiotensin II. We showed that RGS2−/− mice are hypertensive, and others identified RGS2 polymorphisms in hypertension patients. To determine how RGS2 regulates BP, we are analyzing mice with global or tissue/cell type‐specific deletion of RGS2. In vascular smooth muscle (VSM), RGS2 functions as a novel effector of NO‐cGMP‐PKG pathway since the absence of RGS2 impairs the ability of PKG to attenuate Gq‐coupled vasoconstrictor signaling and promote VSM relaxation. Furthermore, PKG phosphorylation of RGS2 augments its GAP activity and association with the plasma membrane. RGS2 also functions in endothelium. We found that ACh‐elicited dilation of mesenteric arteries (MA) from RGS2−/− mice is strikingly impaired. In contrast, ACh‐induced vasodilation was nearly normal in MA from mice lacking RGS2 only in VSM. In RGS2−/− MA, ACh‐induced vasodilation was sensitive to L‐NAME but insensitive to EDHF inhibitors, suggesting that EDHF but not NO production is impaired due to the absence of RGS2. RGS2 deficiency therefore contributes to hypertension by impairing VSM response to NO and blunting endothelial EDHF production. Financial Support from AHA 09POST2260099 to P.O. and NIH GM‐44592 and HL‐075632 to K. J. Blumer.