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

Abstract

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 alpha(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 EC(50). 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.

Selectively Engaging β-Arrestins at the Angiotensin II Type 1 Receptor Reduces Blood Pressure and Increases Cardiac Performance

“…In vivo, acute AT1R-mediated blood pressure effects are regulated by G protein-stimulated calcium mobilization (Harris et al, 2007;Wynne et al, 2009). Consistent with this, and with the in vitro findings in Fig.…”

Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances α1D-adrenergic receptor constriction

“…Mice were anesthetized as described above, the left kidney, renal artery, and vein were exposed via a lower left flank incision, and careful separation of the renal artery and vein enabled the placement of a stainless steel U-shaped clip (0.12 mm inner diameter) to be placed around the renal artery (18,54). 5-0 vicryl sutures closed the incision.…”

Renal Actions of RGS2 Control Blood Pressure

“…6,7 This conclusion was consistent with other studies suggesting that alterations in vascular signaling pathways are necessary and sufficient to mediate hypertension. [12][13][14][15][16][17][18][19] However, previous work by Guyton 20 suggests that chronic peripheral vasoconstriction alone should not be sufficient to cause hypertension. This view is on the basis of the idea that the sodium excretory capacity of the kidney provides a compensatory system with virtually infinite gain for countermanding elevations in BP from other causes including changes in peripheral vascular resistance.…”