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

Mary Tang, Guang Wang, Ping Lu, Richard H. Karas, Mark Aronovitz, Scott P. Heximer, Kevin M. Kaltenbronn, Kendall J. Blumer, David P. Siderovski, Yan Zhu, Michael E. Mendelsohn

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293 Scopus citations

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.

Original languageEnglish
Pages (from-to)1506-1512
Number of pages7
JournalNature Medicine
Volume9
Issue number12
DOIs
StatePublished - 1 Dec 2003

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    Tang, M., Wang, G., Lu, P., Karas, R. H., Aronovitz, M., Heximer, S. P., Kaltenbronn, K. M., Blumer, K. J., Siderovski, D. P., Zhu, Y., & Mendelsohn, M. E. (2003). Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nature Medicine, 9(12), 1506-1512. https://doi.org/10.1038/nm958