Chronic Treatment with the G Protein-Coupled Receptor 30 Agonist G-1 Decreases Blood Pressure in Ovariectomized mRen2.Lewis Rats

Abstract

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.

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein–Coupled Estrogen Receptor

“…[51][52][53] Thus, we considered whether GPER expression would be similarly downregulated in vivo after vascular injury and the consequent shift of VSMCs to the synthetic phenotype. On SDS-PAGE, in carotid artery lysates, GPER was resolved in 2 bands, namely, a major band with a corresponding molecular weight of ≈ 50 kDa-as previously described in other tissues- 54 and a minor band of GPER (≈43 kDa) as reported by other investigators. 55,56 As we have seen in vitro, with VSMC primary culture, after carotid ligation or vascular injury, there was a detectable downregulation of GPER content both with regard to protein content (to 15±6% of control; n=3; Figure 3D) and mRNA content (to 28±3% of control; n=3; Figure 3E).…”

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…Treatment with the selective agonist G‐1 reduces atherosclerosis in ovariectomized mice, and the beneficial effects of GPER in this model are associated with a reduction in macrophage and T‐cell recruitment, indicating an anti‐inflammatory mechanism 55. In addition, activation of GPER has been reported to protect female mice from salt‐ and pressure‐induced vascular damage 56, 57. Altogether, although activation of nuclear, but not membrane, ERα is necessary to induce a protection against atherosclerosis and hypertension, we cannot exclude the participation of other membrane‐initiated steroid signal elicited through GPER‐mediated pathway.…”

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…Interestingly, the expression levels of both GPER and HIF-1α were found to be increased in spontaneously hypertensive rat hearts compared to normotensive controls, suggesting that HIF-1α/ GPER signaling may represent a transduction mediator in certain conditions characterized by elevated blood pressure (74), which is tightly linked to hypoxia (82). Of note, the selective GPER agonist G-1 markedly lowered blood pressure in normotensive and hypertensive rats (83,84), thus supporting the hypothesis that GPER may be a valuable pharmacological target for the prevention/treatment of certain cardiovascular diseases. Further supporting the role elicited by GPER in hypoxic conditions, previous studies have reported that its activation may attenuate the detrimental effects induced by oxygen deficiency in some areas of the central nervous system like the hypothalamic-pituitary axis, hippocampal formation, brainstem autonomic nuclei, and spinal cord (85,86).…”