Nature Medicine9, 1506 - 1512 (2003)
Published online: 9 November 2003; | doi:10.1038/nm958
There is a Corrigendum (January 2004) associated with this Article.
Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure
Mary Tang1, Guang Wang1, Ping Lu1, 4, Richard H Karas1, Mark Aronovitz1, Scott P Heximer2, Kevin M Kaltenbronn2, Kendall J Blumer2, David P Siderovski3, Yan Zhu1, 4
& Michael E Mendelsohn1
1
Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
2
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
3
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
4
Present address: Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I- (PKGI-), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI- 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- binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of Gq, terminating PAR-1 signaling. Disruption of the RGS-2−PKGI- 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- 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.
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