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

Nature Medicine volume 9, pages 15061512 (2003) | Download Citation

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  • A Corrigendum to this article was published on 01 January 2004

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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Author notes

    • Ping Lu
    •  & Yan Zhu

    Present address: Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.

Affiliations

  1. Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

    • Mary Tang
    • , Guang Wang
    • , Ping Lu
    • , Richard H Karas
    • , Mark Aronovitz
    • , Yan Zhu
    •  & Michael E Mendelsohn
  2. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    • Scott P Heximer
    • , Kevin M Kaltenbronn
    •  & Kendall J Blumer
  3. Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • David P Siderovski

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael E Mendelsohn.

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https://doi.org/10.1038/nm958