TY - JOUR
T1 - Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure
AU - Tang, Mary
AU - Wang, Guang
AU - Lu, Ping
AU - Karas, Richard H.
AU - Aronovitz, Mark
AU - Heximer, Scott P.
AU - Kaltenbronn, Kevin M.
AU - Blumer, Kendall J.
AU - Siderovski, David P.
AU - Zhu, Yan
AU - Mendelsohn, Michael E.
N1 - Funding Information:
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.
PY - 2003/12
Y1 - 2003/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=10744233990&partnerID=8YFLogxK
U2 - 10.1038/nm958
DO - 10.1038/nm958
M3 - Article
C2 - 14608379
AN - SCOPUS:10744233990
SN - 1078-8956
VL - 9
SP - 1506
EP - 1512
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -