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Despite the historical dogma that premenopausal women are protected from cardiovascular disease, clinical and experimental evidence indicate that obesity abolishes this protection, placing women at increased risk for hypertension. Previously, our laboratory demonstrated that the adipokine leptin contributes to obesity-associated hypertension in both males and females but via sex specific mechanisms: leptin-mediated sympatho-activation in males and leptin-induced aldosterone production in females. However, the origin of these sex-specific mechanisms remains unknown. Therefore, we aimed to test the contribution of both sex hormones and chromosomes. Female sex hormones were preserved (sham) or depleted via ovariectomy (OVX) in lean control and obese female agouti yellow mice. Blood pressure (BP) recording via radiotelemetry indicated that obesity increased BP (2-way ANOVA, p<0.0001) but OVX did not alter BP in agouti mice. Vascular function measured via mesenteric wire myography indicated obesity impaired (3-way ANOVA, p<0.05) endothelial-dependent relaxation but OVX did not inflict further impairment in agouti mice. OVX did not alter plasma aldosterone levels or adrenal aldosterone synthase (CYP11B2) expression in agouti mice. Leptin receptor blockade (Allo-Aca) decreased BP (2-way ANOVA, p<0.05), restored endothelial-dependent relaxation and decreased (2-way ANOVA, p<0.05) adrenal CYP11B2 expression in both intact and OVX agouti mice indicating a preservation of leptin-mediated BP elevation in the absence of female sex hormones and ruling out sex steroids as the origin of the sex specific mechanisms. Additionally, neither estrogen, progesterone, a combination of estrogen and progesterone, or dihydrotestosterone increase CYP11B2 expression in primary isolated human adrenal cells in culture further supporting that sex hormones do not mediate aldosterone production. These data suggest female sex hormones are not the source for the sex difference prompting us to utilize the four-core genotype (FCG) mouse model to assess the role of sex chromosomes. In order to mimic obesity conditions, BP was recorded at baseline and in response to leptin infusion in OVX FCG XX and XY female mice (XXF and XYF). XX females displayed higher baseline BP than XY (XXF: 109.1±2.4 vs. XYF: 100.4±1.1 mmHg, p<0.05) but leptin infusion increased BP and concurrently ablated the difference. Similarly, XXF displayed heightened plasma aldosterone (2-way ANOVA, 183.7±27 vs. 89.4±34 pg/mL, p<0.05) but leptin infusion abolished the difference. Collectively, these results indicate that XX chromosome rather than female sex steroid hormones regulates aldosterone production, and that sex chromosomes are likely the source for the sexual dimorphism in the mechanism for hypertension associated with obesity. R01HL130301, R01HL155265 (E.J.B.) F31HL168963-01 (C.T.B.). This is the full abstract presented at the American Physiology Summit 2024 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.
Barris et al. (Wed,) studied this question.