ANGIOTENSIN-II AND STRUCTURAL REMODELING OF CORONARY VESSELS IN RATS

A perivascular fibrosis of intramyocardial coronary arterioles, compos ed of type I fibrillar collagen, is associated with chronic elevations in circulating angiotensin II (AngII). The hypothesis tested herein i s that coronary vascular remodeling involving cardiac interstitial fib roblasts is responsible for this fibrous tissue response. This morphol ogic study therefore had several objectives: (1) to determine whether a continuous infusion of AngII (150 ng/min/kg) would alter plasma fibr onectin (pFN) labeling of coronary vessels, and to identify the level of the coronary vasculature Involved in this response; (2) to determin e whether the chronic administration of AngII would ultimately lead to enhanced type I collagen synthesis and a perivascular fibrosis of art erioles, and to identify the cellular response associated with this fi brogenesis. Accordingly, the hearts of rats receiving AngII over the c ourse of 2 weeks were examined at 1, 2, 4, 7, 10, and 14 days. From th e same heart, serial sections were obtained for pFN immunofluorescent microscopy, PCNA immunolabeling, in situ hybridization with a type I c ollagen probe, and light microscopy to address cellular response (hema toxylin and eosin) and formation of fibrillar collagen (picrosirius re d). We found (1) increased coronary arteriolar staining with pFN antib ody on day 2, with an increasing number of vessels involved over 14 da ys; (2) pFN appearing first in the media and adventitia and subsequent ly the interstitial space; (3) fibroblast proliferation on days 2 and 4, and enhanced expression of type I collagen mRNA in these adventitia l and interstitial cells on days 4 and 7; (4) accumulation of macropha ges in the adventitia of involved vessels during the period of observa tion; and (5) a perivascular fibrosis of involved vessels on day 14. T hus we would conclude that the perivascular fibrosis of intramyocardia l coronary arterioles seen in response to chronic elevations in plasma AngII is the outcome of this structural remodeling, which is mediated by type I collagen-producing fibroblasts that have recently divided. The signal(s) that mediates fibroplasia and fibrogenesis and the mecha nism whereby AngII enhances vascular remodeling remain to be elucidate d.