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

Nat Med. 2003 Dec;9(12):1506-12. doi: 10.1038/nm958. Epub 2003 Nov 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Pressure / physiology*
  • Cell Line
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Relaxation / physiology*
  • Muscle, Smooth, Vascular / physiology*
  • RGS Proteins / deficiency
  • RGS Proteins / genetics
  • RGS Proteins / physiology*
  • Rats
  • Receptor, PAR-1 / physiology
  • Signal Transduction


  • RGS Proteins
  • Receptor, PAR-1
  • Rgs2 protein, mouse
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases
  • PRKG1 protein, human
  • Prkg1 protein, mouse