Abstract MP26: Angiotensin-(1-7) Increases Vascular Beta-2 Adrenergic Receptor Expression In Aging Mice

Abstract

Aging is associated with increased sympathetic tone, which desensitizes vascular beta-2 adrenergic receptors (B2AR) to impair vasodilation and promote hypertension. We recently demonstrated that chronic treatment with angiotensin (Ang)-(1-7), a protective hormone of the renin-angiotensin system, decreases blood pressure and cardiac sympathetic tone in aging mice. In this study, we hypothesized that sympathoinhibitory effects of Ang-(1-7) would restore vascular B2AR expression to lower blood pressure in aging. To test this, aging (16-month-old) and young (2-month-old) male C57BL/6J mice received Ang-(1-7) [400 ng/kg/min, n=4] or saline (n=4) infusion for 6 weeks via subcutaneous osmotic mini-pump. At end of treatment, alpha- and beta-adrenergic receptor gene expression was measured in mesenteric arteries, thoracic aorta, and cardiac tissue by quantitative real-time PCR and quantified with 2-ΔΔCT methods. In a separate experiment, male C57BL/6J mice received a single subcutaneous injection of Ang-(1-7) (2 mg/mg, n=4), saline (n=3), or the B2AR antagonist ICI 118,551 (1 mg/kg) plus Ang-(1-7) (n=3). Blood pressure was measured via a carotid artery catheter at baseline and post-treatment. We found that aging mice have decreased mesenteric B2AR gene expression, which was restored by Ang-(1-7) (young saline: 1.04±0.35; aged saline: 0.46±0.17; aged Ang-(1-7): 1.04±0.31 A.U., p=0.026). As a control, Ang-(1-7) did not induce significant changes in B2AR mRNA in thoracic aorta or cardiac tissue, or changes in other adrenergic receptor subtypes (alpha1 or beta1) in any of the tissues studied in aging mice (p>0.05). We further found that depressor effects of acute Ang-(1-7) in mice are attenuated by B2AR blockade (saline: Δ -11±4 mmHg; Ang-(1-7): Δ -26±3 mmHg; ICI 118,551+Ang-(1-7): Δ -4±4 mmHg, p=0.009). Overall, these findings suggest that Ang-(1-7) restores B2AR expression in mesenteric resistance vessels in aging mice, and depressor effects of acute Ang-(1-7) are partially mediated by B2AR. These data support the concept that Ang-(1-7) decreases blood pressure in aging by restoring B2AR-mediated vasodilation. More broadly, Ang-(1-7) may provide a novel treatment target for age-related hypertension and cardiovascular disease.