Stretch-induced TRPC4 downregulation is accompanied by reduced capacitative Ca2+ entry in WKY but not SHR mesenteric smooth muscle cells.

Our previous work showed that a 6-hour cyclic stretch significantly decreases TRPC4 protein expression and capacitative Ca(2+) entry in vascular smooth muscle cells from Sprague-Dawley rats. To parallel these studies, mesenteric smooth muscle cells from spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar Kyoto (WKY) rats, were subjected to stretch. TRPC4 protein expression was evaluated by Western blot and Ca(2+) mobilization was measured using fura-2. As in Sprague-Dawley cells, a 6-hour stretch resulted in a significant down-regulation of TRPC4 protein in both SHR and WKY mesenteric smooth muscle cells. While WKY cells showed a stretch-induced decrease in Ca(2+) dynamics to accompany the reduction in TRPC4 expression, mesenteric smooth muscle cells from SHR showed a stretch-induced increase in both the release of stored Ca(2+) and capacitative Ca(2+) entry. TRPC4 proteins may be working as store-operated channels in normotensive vascular smooth muscle cells and their down-regulation by stretch may be a protective mechanism to prevent additional Ca(2+) influx during stretch. The stretch-induced increase in capacitative Ca(2+) entry in SHR may be due to a compensatory upregulation of non-TRPC4 channels or an increase in store-operated signaling or channel activity.

Chronic treatment with the G protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats.

The mRen2.Lewis congenic strain is an estrogen-sensitive model of hypertension whereby estrogen depletion produces a significant and sustained increase in blood pressure. The recent identification of G protein-coupled receptor 30 (GPR30) as a third estrogen receptor isotype prompted us to test the hypothesis that this novel receptor exhibits beneficial cardiovascular actions in the hypertensive female mRen2.Lewis rat. Intact female, ovariectomized female (OVX), and male mRen2.Lewis rats were treated with the selective GPR30 agonist G-1 or vehicle via osmotic minipump for 2 wk. G-1 significantly reduced systolic blood pressure in OVX (178 +/- 7 to 142 +/- 10 mm Hg, P < 0.001, n = 8) but not intact female (144 +/- 3 to 143 +/- 5 mm Hg, P > 0.05, n = 5) or male mRen2.Lewis rats (207 +/- 7 to 192 +/- 5 mm Hg, P > 0.05, n = 7). G-1 did not alter uterine or body weight in OVX, suggesting activation of a receptor distinct from estrogen receptor-alpha and -beta. In isolated aortic rings from OVX, G-1 reduced constriction in response to angiotensin II. Vascular angiotensin-converting enzyme and angiotensin type 1 receptor mRNA were also lower, whereas angiotensin-converting enzyme-2 mRNA was increased. G-1 treatment in OVX was not associated with alterations in either endothelial nitric oxide synthase expression or acetylcholine-induced relaxation. Immunohistochemical staining for GPR30 was evident in both the intima and media of the aorta. We conclude that the novel estrogen receptor GPR30 may contribute to the beneficial cardiovascular actions of estrogen in female mRen2.Lewis rats through regulation of vascular components of the renin-angiotensin system.