396 ANGIOTENSIN (ANG) TYPE 2 RECEPTOR (AT2R) REGULATES AORTIC SMOOTH MUSCLE CELL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR GAMMA) EXPRESSION IN VIVO IN APOLIPOPROTEIN (APO) E-DEFICIENT MICE

Abstract

Objectives: AT2R deficiency exacerbates atherosclerotic progression in ApoE(–/–) mice. Because AT2Rs are low/undetectable in wild-type (WT) C57BL/6 aortas we hypothesize that ApoE regulates vascular AT2Rs. Methods: We measured AT2Rs (using quantitative-immunofluorescence) in aortic arch vascular smooth muscle (VSMC) and endothelial cell (EC) layers and mean arterial blood pressure (MAP) in anesthetized mice. Nine-week-old ApoE(–/–) and WT mice were fed a low (LC) or high cholesterol (HC) diet for 1 week. Animals were administered vehicle or Ang II (12 μg/kg/hr), with or without PD123319 (10 mg/kg/day) (AT2R antagonist) for 7 days. Results: In LC/ApoE(–/–) vs. WT mice, VSMC and EC AT2R was 80- and 26-fold higher (P < 0.001). HC increased serum cholesterol ∼2-fold (P < 0.001) and decreased VSMC AT2R levels 9.5-fold (P < 0.01) in ApoE(–/–) mice. Low-dose Ang II infusion, which was without effect in LC/WT mice decreased MAP by 15% in LC/ApoE(–/–) (79 ± 2 vs. 67 ± 3 mmHg, vehicle vs. Ang II, respectively; n = 10/gp., P < 0.01) but not HC/ApoE(–/–) mice (82 ± 3 vs. 80 ± 2 mmHg vehicle vs. Ang II, respectively; n = 7-11/gp.). A study of vasodilator mechanisms indicated that low-dose Ang II caused a ∼6-fold increase in VSMC, but not EC, PPAR-γ (P < 0.001) in LC/ApoE(–/–) mice; both VSMC and EC phospho-nitric oxide synthase were not significantly changed. These effects were blocked by PD123319. Conclusions: Our findings suggest that ApoE-deficiency initiates vascular protective effects of AT2R by increasing its expression, and that a HC diet blocks this up-regulation making the vasculature more prone to atherosclerosis.