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

In the vasculature, the angiotensin type 2 (AT2) receptor (AT2R) exerts antiproliferative, antifibrotic, and proapoptotic effects. Normal adult animals have low AT2R expression; however, vascular injury and exposure to proinflammatory cytokines augment AT2R levels. We hypothesized that AT2R expression increases during initiation and progression of atherosclerosis. Atherosclerotic lesions of apolipoprotein (Apo) E(-/-) mice contained AT2Rs, 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 (Agtr2+) 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. Thus, loss of AT2R during the evolution of atherosclerotic lesions augmented the extent of cellularity of atherosclerotic lesions, establishing AT2R as a modulator of atherogenesis.