Loss of Female Sex Hormones Does Not Induce a Mechanistic Switch for Development of Hypertension in Obese Female Mice

Abstract

Hypertension is a leading risk factor for cardiovascular disease (CVD), affecting more than 75% of postmenopausal women. Obesity, a significant risk factor for developing hypertension and CVD, is present in approximately 40% of postmenopausal women. Despite extensive studies on the mechanisms of hypertension, the mechanisms whereby obesity and menopause interact to elevate blood pressure (BP) in women remain unknown. Previous studies from our laboratory have demonstrated that obesity-associated hypertension is dependent on leptin in both males and females but involves sex-specific mechanisms: leptin-mediated sympatho-activation in males and leptin-induced aldosterone production in females. As estrogen blunts sympathetic activity, we hypothesized that loss of female sex hormones with ovariectomy (OVX) induces a switch in the mechanisms of hypertension from aldosterone to sympatho-mediated in obese mice. Obese yellow agouti mice (Ay) on a KK background underwent OVX or sham surgery at 12 weeks of age. BP recording via radiotelemetry revealed no elevation in BP (Sham: 119±2.9 vs. OVX: 116±7.7 mmHg) or heart rate (HR, Sham: 622±17 vs. OVX: 592±17 bpm) in response to OVX. To investigate the effects of OVX on sympatho-activation, we measure BP and HR responses to ganglionic blockade (hexamethonium) as well as to atropine and propranolol. Surprisingly, we observed no alteration in the drop in mean arterial pressure (MAP) and the increase in HR in response to hexamethonium, propranolol and atropine respectively after OVX. Mice then underwent seven days treatment with Allo-Aca, a leptin receptor antagonist (0.05mg/kg/day s.c. osmotic minipump). Allo-Aca decreased BP to a similar extent in sham and OVX mice, though not significantly. BP data was again recorded in response to ganglionic blockade and atropine but neither OVX nor leptin receptor antagonist treatment elicited significant differences on HR or MAP responses. Endothelial function was experimentally measured by wire myography concentration response curves to acetylcholine in mouse thoracic aorta. Endothelial function in OVX mice (n=3) showed a trend to being impaired compared to sham mice (n=4) (2-way ANOVA, P<0.17). Relaxation responses to acetylcholine in the presence of LNAME indicated that endothelial dysfunction in OVX mice was not attributable to reduction in nitric oxide activity. Collectively, this preliminary data suggest that obese ovariectomized mice may not undergo a mechanistic shift for the development of hypertension in response to the absence of female sex hormones and may continue to develop endothelial dysfunction via aldosterone-dependent mechanisms.