Ovariectomy Augments Hypertension Through Rho-Kinase Activation in the Brain Stem in Female Spontaneously Hypertensive Rats

Abstract

Estrogen protects against increases in arterial pressure (AP) by acting on blood vessels and on cardiovascular centers in the brain. The mechanisms underlying the effects of estrogen in the brain stem, however, are not clear. The aim of the present study was to determine whether ovariectomy affects AP via the Rho/Rho-kinase pathway in the brain stem. We performed bilateral ovariectomy in 12-week-old female spontaneously hypertensive rats. AP and heart rate (HR), measured using radiotelemetry in awake rats, were increased in ovariectomized rats compared with control rats (mean AP: 163±3 versus 144±4 mm Hg; HR: 455±4 versus 380±6 bpm). Continuous intracisternal infusion of Y-27632 significantly attenuated the ovariectomy-induced increase in AP and HR (mean AP: 137±6 versus 163±3 mm Hg; HR: 379±10 versus 455±4 bpm). In addition, we confirmed the increase of Rho-kinase activity in the brain stem in ovariectomized rats, and the increase was attenuated by intracisternal infusion of Y-27632 via the phosphorylated ezrin, radixin, and moesin (ERM) family, which are Rho-kinase target proteins. Furthermore, angiotensin II type 1 receptor expression in the brain stem was significantly greater in ovariectomized rats than in control rats, and the increase was partially reduced by intracisternal infusion of Y-27632. In a separate group of animals, we confirmed that the serum and cerebrospinal fluid 17β-estradiol concentrations decreased in ovariectomized rats. These results suggest that depletion of endogenous estrogen by ovariectomy, at least in part, induces hypertension in female spontaneously hypertensive rats via activation of the renin–angiotensin system and the Rho/Rho-kinase pathway in the brain stem.