Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure

Nitric oxide (NO) inhibits vascular contraction by activating cGMP- dependent protein kinase I-alpha (PKGI-alpha), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-alpha attenuates signaling by the thrombin receptor protease- activated receptor- 1 (PAR- 1) through direct activation of regulator of G- protein signaling- 2 (RGS- 2). NO donors and cGMP cause cGMP- mediated inhibition of PAR- 1 and membrane localization of RGS- 2. PKGI-alpha binds directly to and phosphorylates RGS- 2, which significantly increases GTPase activity of G(q), terminating PAR- 1 signaling. Disruption of the RGS- 2- PKGI-alpha interaction reverses inhibition of PAR- 1 signaling by nitrovasodilators and cGMP. Rgs2(-/-) mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-alpha binds to, phosphorylates and activates RGS- 2, attenuating receptor- mediated vascular contraction. Our study shows that RGS- 2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.