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Am J Physiol Endocrinol Metab. 2015 Jun 15;308(12):E1066-75. doi: 10.1152/ajpendo.00030.2015. Epub 2015 Apr 14.

Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism.

Author information

1
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
2
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky lcassis@uky.edu.

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.

KEYWORDS:

17β-estradiol; blood pressure; ovariectomy; renin-angiotensin system

PMID:
26078188
PMCID:
PMC4469807
DOI:
10.1152/ajpendo.00030.2015
[Indexed for MEDLINE]
Free PMC Article

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