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Vascular smooth muscle G_q signaling is involved in high blood pressure in both induced renal and genetic vascular smooth muscle-derived models of hypertension

Eugene Feiner Laboratory of Vascular Biology and Thrombosis, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 26 July 2007 ; accepted in final form 13 September 2007

More than 30% of the US population has high blood pressure (BP), and less than a third of people treated for hypertension have it controlled. In addition, the etiology of most high BP is not known. Having a better understanding of the mechanisms underlying hypertension could potentially increase the effectiveness of treatment. Because G_q signaling mediates vasoconstriction and vascular function can cause BP abnormalities, we were interested in determining the role of vascular smooth muscle (VSM) G_q signaling in two divergent models of hypertension: a renovascular model of hypertension through renal artery stenosis and a genetic model of hypertension using mice with VSM-derived high BP. Inhibition of VSM G_q signaling attenuated BP increases induced by renal artery stenosis to a similar extent as losartan, an ANG II receptor blocker and current antihypertensive therapy. Inhibition of G_q signaling also attenuated high BP in our genetic VSM-derived hypertensive model. In contrast, BP remained elevated 25% following treatment with losartan, and prazosin, an ₁-adrenergic receptor antagonist, only decreased BP by 35%. Inhibition of G_q signaling attenuated VSM reactivity to ANG II and resulted in a 2.4-fold rightward shift in EC₅₀. We also determined that inhibition of G_q signaling was able to reverse VSM hypertrophy in the genetic VSM-derived hypertensive model. These results suggest that G_q signaling is an important signaling pathway in two divergent models of hypertension and, perhaps, optimization of antihypertensive therapy could occur with the identification of particular G_q-coupled receptors involved.

two-kidney, one-clip renovascular hypertension; G protein-coupled receptor kinase 2; seven transmembrane-spanning receptor

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