Differential Effects of Angiotensin II on Cardiac Cell Proliferation and Intramyocardial Perivascular Fibrosis In Vivo

BACKGROUND: Growth effects of angiotensin II (Ang II) contribute to cardiac remodeling. Remodeling, in turn, may be influenced by proliferation of nonmyocytes. The aims of this study were to determine in vivo which cardiac cell types proliferate in response to Ang II, to evaluate whether proliferation is mediated by the Ang II AT1 receptor, and to establish whether blood pressure affects cell proliferation by comparing proliferation in the normotensive right atrium and ventricle and pressure-overloaded left ventricle. METHODS AND RESULTS: Groups of 8 Wistar rats were implanted with miniosmotic pumps releasing 5-bromo-2'-deoxyuridine (BrdU) as a cell proliferation marker for 2 weeks. Two groups received Ang II infusions via a second minipump and drinking water+/-losartan. Two groups received vehicle+/-losartan. Cell proliferation was assessed as the percentage of nuclei that incorporated BrdU. Ang II increased proliferation within medial vascular smooth muscle cells (VSMCs) and in associated adventitial/interstitial fibroblasts of intramyocardial coronary arterioles but decreased proliferation of myoendothelial cells. Despite increased blood pressure, proliferation in atria and ventricles was similar. Aldosterone levels were not significantly elevated, suggesting direct proliferative effects of Ang II. Losartan reduced Ang II-induced VSMC and adventitial fibroblast proliferation but had no effect on myoendothelial cell proliferation. CONCLUSIONS: These results indicate direct, differential effects of Ang II on proliferation of atrial and ventricular nonmyocytes. VSMC and fibroblast proliferation is AT1 receptor-dependent, whereas myoendothelial cells are controlled by an AT1-independent mechanism. The effects are independent of aldosterone and blood pressure and have important implications in renin-dependent hypertension and chronic cardiac failure when circulating Ang II is elevated.