Ovarian-derived sex hormones do not mediate the sex-specific mechanism of hypertension in obese mice
Authors: Barris Candee , Kress Taylor , Antonova Galina , Faulkner Jessica , Belin de Chantemele Eric 
Published: May 2023

The longstanding dogma that female sex hormones protect premenopausal women against cardiovascular disease perpetuated the belief that sex hormones are the main determinant for cardiovascular risk. However, increasing global trends for obesity and recent clinical evidence indicate that obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Previously, our laboratory demonstrated that obesity-associated hypertension manifests via sex-specific mechanisms: leptin-mediated sympatho-activation in males and leptin-mediated aldosterone production in females. Whether sex hormones are the source for these sex differences remains unknown. We hypothesized that loss of ovarian-derived sex hormones with ovariectomy (OVX) will alter the mechanism by which obese female mice develop hypertension and impair vascular function. Obese agouti yellow mice and lean controls underwent OVX or sham surgery at 12 weeks. At 15 weeks of age, mice were implanted with radiotelemeters to record blood pressure (BP) at baseline and in response to leptin receptor blockade (Allo-Aca, 0.05mg/kg/day s.c. osmotic minipump). To determine the effect of OVX on autonomic control of BP, we recorded BP and heart rate (HR) responses to ganglionic blockade, muscarinic and β-adrenergic receptor antagonists. At 18 weeks, mice were euthanized and mesenteric arteries isolated to measure vascular function via wire myography. Obesity significantly increased (2-way ANOVA, P<0.05) mean arterial pressure (MAP), systolic BP, diastolic BP, and HR but surprisingly OVX did not further elevate BP. However, leptin receptor blockade significantly decreased (2-way ANOVA, P<0.05) MAP in obese mice, indicating that BP elevation remains leptin-dependent in OVX obese female mice. OVX did not alter MAP or HR responses to ganglionic blockade, muscarinic and β-adrenergic receptor antagonists, suggesting no further contribution of autonomic control of BP. Mesenteric wire myography revealed obesity significantly impaired (2-way ANOVA, P<0.05) endothelial-dependent relaxation to acetylcholine but interestingly, loss of ovarian-derived sex hormones did not cause further impairment. Western blot analysis showed no alteration in adrenal aldosterone synthase expression in obese OVX mice and LC-MS revealed no difference in plasma aldosterone levels. These results indicate that in the absence of ovarian-derived female sex hormones, hypertension remains leptin-dependent and aldosterone-mediated in obese female mice and female sex steroids likely play a limited role. This work challenges the notion that sex hormones mediate the sex-specific mechanism of hypertension in the context of obesity suggesting sex chromosomes as the underlying origin for the difference in mechanism. R01HL130301, R01HL155265 (E.J.B.) T32 HL155011-01A1 (C.T.B.) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.