In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism

Supplemental Digital Content is available in the text. Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT2R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT2R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E2)–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT2R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E2-treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P=0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females (P=0.01). E2-treatment reduced the Ang II pressor response in aged females (P=0.002), an effect that was reversed by PD123319 in the aged E2–Ang II group (P=0.0009). E2-treatment increased renal AT2R (≈6-fold; P<0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P<0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E2-treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT2R-mediated renal mechanism.