Ligand-dependent activation of ER lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats

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Abstract
The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERα and ERβ, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERα agonist 16α-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERβ-deficient mice exhibit elevated blood pressure and since the ERβ agonist 8β-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERβ agonist 8β-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR. Treatment of ovariectomized SHR with 8β-VE2 for 12 weeks conferred no uterotrophic effects but lowered elevated systolic blood pressure (−38 ± 5 mmHg, n = 31, P < 0.001 vs. placebo) as well as peripheral vascular resistance (−31.3 ± 4.6%, P < 0.001 vs. placebo). 8β-VE2 enhanced aortic ERβ expression (+75.7 ± 7.1%, P < 0.01 vs. placebo), improved NO-dependent vasorelaxation, augmented phosphorylation of the vasodilator-stimulated phosphoprotein in isolated aortic rings (P < 0.05 vs. placebo), increased cardiac output (+20.4 ± 2.5%, P < 0.01 vs. placebo), and attenuated cardiac hypertrophy (−22.2 ± 3.2%, p < 0.01 vs. placebo). 8β-VE2, in contrast to oestradiol, did not enhance cardiac α-myosin heavy chain expression. Ligand-dependent activation of ERβ confers blood pressure lowering effects in SHR that are superior to those of 17β-estradiol or the ERα agonist 16α-LE2 and attenuates cardiac hypertrophy primarily by a reduction of cardiac afterload without promoting uterine growth.

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