Is β the α Dog in Estrogen Receptor–Mediated Protection From Hypertension?

Abstract

T he onset of hypertension occurs earlier in men than in women. Moreover, the magnitude of hypertension is greater in men than in women across diverse mammalian species and experimental models. 1 17β-estradiol (E 2 ) is implicated in this female protection because ovarian hormone loss is associated with increased arterial pressure while E 2 replacement can prevent this effect. Creation of mice deficient in estrogen receptors (ERα and ERβ) and the development of ER subtypeselective ligands have enabled investigation of ER subtypes in hypertension.A study of Japanese women revealed an association between hypertension and a cytosine-adenine repeat polymorphism in the ERβ gene.2 This association was strengthened by studies in ERβ-deficient mice, which developed hypertension as they aged and exhibited abnormal ion channel function in vascular smooth muscle cells suggesting ERβ attenuated the age-associated hypertension by preserving vascular function.3 Pharmacological studies supported these conclusions by demonstrating selective agonists of ERβ-reduced arterial pressure in ovariectomized spontaneously hypertensive rats under conditions in which ERα-selective agonists did not. 4 Furthermore, activation of ERβ improved nitric oxide-dependent vasorelaxation, increased cardiac output, and attenuated cardiac hypertrophy; however, this study did not determine whether these effects were peripherally or centrally mediated.Previously, Xue et al 5 showed that central but not peripheral infusions of a nonselective ER antagonist into mice augmented the pressor effects of angiotensin II (Ang II), thereby underscoring the importance of central ERs in blood pressure modulation. In this issue, Xue et al 6 used small interference RNA via an adeno-associated virus to selectively knockdown ERα and ERβ in specific brain nuclei. Mice with ERβ deficiency in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) exhibited increased sympathetic activity during mineralocorticoid excess. In contrast, ERα knockdown in these same nuclei had no effect on sympathetic activity during aldosterone treatment and sodium loading. In addition, they showed that pharmacological activation of neuronal ERβ but not ERα reduced arterial pressure under these conditions. Using this complementary approach, they addressed a caveat associated with nuclei-specific siRNA technology, namely, that remaining ERα after incomplete knockdown may be sufficient to mimic the actions of the ERα-replete wild-type mice. These findings elegantly demonstrate ERβ-specific effects on central autonomic control of arterial pressure during mineralocorticoid excess.The authors propose that inhibition of superoxide anion in the PVN contributes to the antihypertensive effects of ERβ on the basis of observing augmented superoxide anion formation after silencing ERβ in cultured PVN neurons treated overnight with aldosterone; however, these ER-observed effects on superoxide generation occurred in the absence of E 2 and were ER subtype independent. These cell culture stu...