Transforming growth factor-beta-dependent events in vascular remodeling following arterial injury

Abstract

Constrictive remodeling has been identified as a major contributor to restenosis following angioplasty. Characterization of transforming growth factor-beta (TGF-beta)-mediated cellular events in the adventitia and their contribution to vascular remodeling, however, has not previously been studied in detail. The balloon catheter denudation model was performed on rat carotid artery, and groups of rats were treated with vehicle or a TGF-beta inhibitor, a soluble TGF-beta receptor type II (TGF-beta R:Fc). Adventitial cell proliferation, which peaked 4 days after injury, was characterized by the de novo formation of several cell layers surrounding the outer adventitia and this process was not dependent upon TGF-beta activity. These neoadventitial cells expressed an abundance of collagen type I and a fetal isoform of fibronectin containing the EIIIA domain, and the expression of both proteins was suppressed in the presence of TGF-beta R:Fc. Lumenal narrowing was apparent 14 days after injury. Inhibition of TGF-beta signaling promoted vessel enlargement. As a result, lumen size did not change despite neointima formation. In conclusion, adventitial fibrosis with abundant collagen matrix deposition but not adventitial cell proliferation is dependent upon endogenous TGF-beta activity. Furthermore, inhibition of TGF-beta signaling prevents injury-induced reduction in lumen area by promoting vessel enlargement.