Abstract
Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-α (PKGI-α), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-α 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-α binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of Gq, terminating PAR-1 signaling. Disruption of the RGS-2–PKGI-α 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-α 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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Acknowledgements
Stably transfected Rat1 fibroblast cells expressing PAR-1 were the kind gift of S. Coughlin. This work was supported in part by National Institutes of Health grants P50 HL63494, NIH R01 HL55309 and NIH R01 HL56069 (M.E.M.); NIH HL56235 and a Grant-in-Aid from the American Heart Association (Y.Z.), and NIH P01 GM65533 and R01 GM62338 (D.P.S.). D.P.S. is Year 2000 Scholar of The EJLB Foundation.
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Tang, M., Wang, G., Lu, P. et al. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med 9, 1506–1512 (2003). https://doi.org/10.1038/nm958
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DOI: https://doi.org/10.1038/nm958
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