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Female Sex Hormones are Not the Source for Sex Differences in the Mechanisms of Obesity-associated Hypertension in Female Agouti Mice

Candee T. Barris, Taylor C. Kress, Jessica L. Faulkner, Eric J. Belin de Chantemèle

Vascular Biology Center, Medical College of Georgia at Augusta University

Historically, it was thought that sex hormones determine the risk for cardiovascular disease (CVD), which perpetuated the longstanding dogma that premenopausal women are protected against CVD. However, recent compelling clinical evidence indicates obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Our laboratory demonstrated that obesity-associated hypertension (OAH) involves leptin, though by sex-specific mechanisms: leptin-mediated sympatho-activation in males and leptin-mediated aldosterone production in females. However, 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 mechanisms by which obese female mice develop OAH and impair vascular function. Obese agouti yellow mice and lean controls underwent OVX or sham surgery at 12 weeks. Radiotelemetry blood pressure (BP) recording revealed that obesity significantly increased mean arterial pressure (MAP), that OVX did not alter BP but leptin receptor blockade significantly decreased MAP in obese mice, indicating that BP elevation remains leptin-dependent in OVX obese female mice. To ascertain female sex hormones contribution on autonomic control of BP in obesity, we recorded BP and heart rate (HR) responses to ganglionic blockade, muscarinic and -adrenergic receptor antagonists. OVX did not alter MAP or HR responses, suggesting no contribution of sex hormones to autonomic control of BP in obese female mice. Wire myography revealed obesity significantly impaired endothelial-dependent relaxation to acetylcholine but OVX 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 mouse plasma aldosterone levels. Therefore, OAH remains leptin-dependent and aldosterone-mediated in the absence of ovarian-derived female sex hormones and female sex steroids likely play a limited role in the control of the mechanisms of hypertension associated with obesity.

Funding: R01HL130301, R01HL155265 (E.J.B.) T32 HL155011-01A1 (C.T.B.)