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

Abstract

See related article, pp 1255–1262 The 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 (E2) is implicated in this female protection because ovarian hormone loss is associated with increased arterial pressure while E2 replacement can prevent this effect. Creation of mice deficient in estrogen receptors (ERα and ERβ) and the development of ER subtype-selective 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 al5 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 al6 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 …