Loss of Female Sex Hormones Does Not Further Elevate Blood Pressure in Obese Female Mice but Preserves the Contribution of Leptin to Hypertension

Candee T. Barris, Taylor C. Kress, Kikelomo Ogun-Semore, Jessica L. Faulkner, Muhammad I. Saeed, Eric J. Belin de Chantemèle

Research output: Contribution to journalArticlepeer-review

Abstract

Obesity, which is a major risk factor for hypertension and cardiovascular disease, abolishes the cardioprotective effects of female sex hormones and predisposes women to hypertension. Although 40% of postmenopausal women are obese and 75% are hypertensive, the mechanisms whereby obesity and menopause interact to elevate blood pressure (BP) remains unknown. Formerly, our laboratory demonstrated that hypertension involves leptin-mediated increases in aldosterone production in obese female mice of reproductive age. Herein, we hypothesized that loss of female sex hormones with ovariectomy (OVX) will further elevate BP and impairs vascular function in obese female mice. Obese agouti yellow mice (Ay) on a KK background and lean controls underwent OVX or sham surgery at 12-week of age. At 15 weeks, mice were implanted with radiotelemeters to record BP under baseline conditions and in response to leptin receptor blockade (Allo-Aca, 0.05mg/kg/day s.c. osmotic minipump). To ascertain the effects of OVX on autonomic control of BP, we recorded BP and heart rate (HR) responses to ganglionic blockade (hexamethonium), atropine, and propranolol. At 18 weeks, mice were euthanized and mesenteric arteries isolated to measure endothelial function via wire myography. Obesity significantly increased mean arterial pressure (MAP), systolic BP, diastolic BP, and HR but OVX did not further elevate BP. Interestingly, obesity also disrupted circadian rhythm. Unexpectedly, OVX significantly reduced MAP response to ganglionic blockade (2-way ANOVA, P<0.05) in obese mice but preserved HR responses to propranolol and atropine respectively suggesting lower neurogenic control of BP. Allo-Aca treatment significantly decreased (2-way ANOVA, P<0.05) MAP in both sham and OVX obese mice, indicating BP elevation remains leptin-dependent. Obesity significantly impaired relaxation to acetylcholine (2-way ANOVA, P<0.05) but OVX did not further impair relaxation. Compared to lean controls, LNAME further reduced (2-way ANOVA, P=0.054) relaxation responses to acetylcholine in obese OVX mice suggesting greater contribution of nitric oxide synthase activity to vascular relaxation. Quantitative real-time PCR showed a trend for decreased adrenal aldosterone synthase (CYP11B2) expression in obese OVX mice. Interestingly, menopause induced a similar decrease in CYP11B2 expression in human adrenal tissue collected from kidney donors with elevated BMIs (postmenopausal 56 yo female: BMI 27.4, vs. premenopausal 43 yo female, BMI 32). Quantification of mouse plasma aldosterone levels via LC-MS revealed no significant difference in circulating aldosterone levels, suggesting that tissue(s) other than the adrenals could potentially produce aldosterone in obese OVX mice. Plasma analysis also revealed Allo-Aca treatment increased ANG II, ANG I and ANG 1-7 in obese mice. In conclusion, these data suggest that obesity-associated hypertension remains leptin dependent in the absence of female sex hormone and that female sex steroids play limited role in the control of the development of hypertension associated with obesity.

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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