Angiotensin Type 2 Receptor Is Expressed in Murine Atherosclerotic Lesions and Modulates Lesion Evolution

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Abstract
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 (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. 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.

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