Angiotensin type 2 receptor is expressed in murine atherosclerotic lesions and modulates lesion evolution

Background-In the vasculature, the angiotensin type 2 (AT(2)) receptor (AT(2)R) exerts antiproliferative, antifibrotic, and proapoptotic effects. Normal adult animals have low AT(2)R expression; however, vascular injury and exposure to proinflammatory cytokines augment AT(2)R levels. We hypothesized that AT(2)R expression increases during initiation and progression of atherosclerosis. Methods and Results-Atherosclerotic lesions of apolipoprotein (Apo) E-/- mice contained AT(2)Rs, measured by real-time polymerase chain reaction and confirmed by immunohistochemistry. To test the consequences of this expression, male ApoE(-/-), angiotensin II type 2 receptor-deficient (Agtr2(-)), and ApoE(-/-), wild-type (Agtr(2+)) mice consumed a high-cholesterol diet from 4 weeks of age. Ten weeks later, overall area and cellular composition of aortic arch lesions did not differ significantly among genotypes. After 16 weeks, ApoE(-/-)/Agtr2(+), but not ApoE(-/-)/Agtr2(-) mice had dramatic decreases in percent positive area of macrophages, smooth muscles, lipids, and collagen. Diminished bromodeoxyuridine incorporation and increased TUNEL staining accompanied these decreases. Conclusions-Thus, loss of AT(2)R during the evolution of atherosclerotic lesions augmented the extent of cellularity of atherosclerotic lesions, establishing AT(2)R as a modulator of atherogenesis.