title: Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism.
abstract: We recently demonstrated that female mice are resistant to the development of obesity-induced hypertension through a sex hormone-dependent mechanism that involved adipose angiotensin-converting enzyme 2 (ACE2). In this study, we hypothesized that provision of 17β-estradiol (E2) to ovariectomized (OVX) high-fat (HF)-fed female hypertensive mice would reverse obesity-hypertension through an ACE2-dependent mechanism. Pilot studies defined dose-dependent effects of E2 in OVX female mice on serum E2 concentrations and uterine weights. An E2 dose of 36 μg/ml restored normal serum E2 concentrations and uterine weights. Therefore, HF-fed OVX female Ace2(+/+) and Ace2(-/-) mice were administered vehicle or E2 (36 μg/ml) for 16 wk. E2 administration significantly decreased body weights of HF-fed OVX female Ace2(+/+) and Ace2(-/-) mice of either genotype. At 15 wk, E2 administration decreased systolic blood pressure (SBP) of OVX HF-fed Ace2(+/+) but not Ace2(-/-) females during the light but not the dark cycle. E2-mediated reductions in SBP in Ace2(+/+) females were associated with significant elevations in adipose ACE2 mRNA abundance and activity and reduced plasma ANG II concentrations. In contrast to females, E2 administration had no effect on any parameter quantified in HF-fed male hypertensive mice. In 3T3-L1 adipocytes, E2 promoted ACE2 mRNA abundance through effects at estrogen receptor-α (ERα) and resulted in ERα-mediated binding at the ACE2 promoter. These results demonstrate that E2 administration to OVX females reduces obesity-induced elevations in SBP (light cycle) through an ACE2-dependent mechanism. Beneficial effects of E2 to decrease blood pressure in OVX obese females may result from stimulation of adipose ACE2.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Robin
authors.initials: R
authors.lastname: Shoemaker
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Thatcher
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Frederique
authors.initials: F
authors.lastname: Batifoulier-Yiannikouris
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: English
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky lcassis@uky.edu.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications*; D010052:Ovariectomy; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D004958:Estradiol; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: 17β-estradiol; blood pressure; ovariectomy; renin-angiotensin system