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

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 AT(2)R (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 AT(2)R-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-17 beta-estradiol (E-2)-treated (3 mu g/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg.min] SC) or Ang II+PD123319 (AT(2)R 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 E-2-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 approximate to 20 mm Hg in aged compared with adult females (P=0.01). E-2-treatment reduced the Ang II pressor response in aged females (P=0.002), an effect that was reversed by PD123319 in the aged E-2-Ang II group (P=0.0009). E-2-treatment increased renal AT(2)R (approximate to 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 E-2-treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT(2)R-mediated renal mechanism.