Cilazapril, a novel long-acting inhibitor of angiotensin-converting enzyme, markedly suppressed the proliferative response and neointima formation after balloon catheter-induced injury of the carotid artery in a rat model of angioplasty. The reduction in neointima was dose-dependent, required sustained high levels of enzyme inhibition, and was significantly greater in animals treated starting 6 days prior to the procedure than in animals starting treatment the day of catheterization. In experiments with vascular smooth-muscle cells (SMC) in culture, the addition of angiotensin II reduces increased mRNA levels for several growth factors and extracellular matrix proteins. Here we report that Ang II selectively induces mRNA for thrombospondin I, but not for thrombospondin II. Under selected conditions SMC can be induced to proliferate after exposure to Ang II, in vitro and in vivo. Using neutralizing anti transforming growth factor β (TGF-β) antibodies we found that Ang II stimulation of proliferation was threefold greater when the anti-TGF-β was added to the cultures. We suggest (a) that an important effect of Ang II during the proliferative response is the induction of thrombospondin I, which is required for matrix interactions during the formation of neointima, and (b) that, among the complex array of growth factors potentially active in vivo, TGF-β may be an important negative regulatory factor that limits the proliferative response and prevents restenosis in most cases of angioplasty.
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