Abstract 533: MAS Receptor Activation Contributes to the Improvement of Vascular Remodeling During Chronic Angiotensin II Type 1 Receptor Blockade in Angiotensin II Type 2 Receptor Knockout Mice.
Angiotensin (Ang)-(1-7) through MAS receptor may counteract the Ang II-induced actions. We previously demonstrated that the Ang receptor blocker olmesartan (OLM) improved vascular remodeling in SHR in part through the activation of MAS receptor. Here, we hypothesized that such an effect is independent of Ang II type 2 (AT2) receptor activation. AT2-knockout mice (AT2-K/O, 12 weeks old, n=6 per group) were treated with vehicle (control) or Ang (1-7) (15,5 pmol/kg/min) or Ang II (400 ng/kg/min) ± OLM (10 mg/kg/day) ± the MAS antagonist A-779 (11 pmol/min) for 14 days. BP was measured by tail-cuff method. In isolated mesenteric arteries pre-contracted with norepinephrine (10 μM) endothelium -dependent and -independent relaxation was assessed by dose-response curves to acetylcholine (1 nM to 100 μM) and SNP (10 nM to 1 mM) respectively. Mesenteric arteries media-to-lumen ratio (M/L) and cross sectional area (CSA) were evaluated on pressurized preparations. MAS expression in aorta was evaluated by immunoblotting. Ang II infusion increased BP in AT2-K/O (+20% vs control mice, P<0.05). OLM reduced BP in Ang II-infused mice (104.8±4.4 mmHg vs 121.3±2.8 mmHg, respectively, P<0.05). A-779 had no effect on BP in Ang II-infused mice treated with OLM. Ang (1-7) did not lower BP in AT2-K/O. Endothelium -dependent and -independent relaxations were similar in treated and control mice. M/L was similar in Ang II-infused and control mice. OLM significantly reduced M/L in Ang II-infused AT2-K/O (5.45±0.12 % vs 7.01±0.4%, respectively, -23%, P<0.05). A-779 increased M/L in Ang II-infused AT2-K/O treated with OLM (+18%, P<0.05). Ang (1-7) reduced M/L in AT2-K/O (-21%, P<0.05). CSA was similar in all the groups. MAS expression was similar in Ang II-infused and control mice. MAS expression was increased by OLM in Ang II-infused mice (+108%, P<0.05). A-779 prevented MAS increase in Ang II-infused mice treated with OLM. Ang (1-7) increased MAS expression in AT2-K/O (+81%, P<0.05). In conclusion OLM reduced M/L and improved vascular remodeling in AT2-K/O in part through the increased expression and activation of MAS, independently of BP reduction. Such an effect is indeed independent of AT2 activation, as MAS is functionally active in the vasculature of AT2-K/O.
- © 2012 by American Heart Association, Inc.