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

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-estra-diol (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^{+I +}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^+I+ and Ace2^-/-mice of either genotype. At 15 wk, E₂ administration decreased systolic blood pressure (SBP) of OVX HF-fed Ace2^+I+ but not Ace2^-/- females during the light but not the dark cycle. E₂-mediated reductions in SBP in Ace2^+I+ females were associated with significant elevations in adipose ACE2 mRNA abundance and activity and reduced plasma ANGII 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 ERa-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.