Soluble transforming growth factor-beta type II receptor inhibits negativeremodeling, fibroblast transdifferentiation, and intimal lesion formation but not endothelial growth

Using the rat balloon catheter denudation model, we examined the role of tr ansforming growth factor-beta (TGF-beta) isoforms in vascular repair proces ses. By en face in situ hybridization, proliferating and quiescent smooth m uscle cells in denuded vessels expressed high levels of mRNA for TGF-beta(1 ), TGF-alpha(2), TGF-beta(3), and lower levels of TGF-beta receptor II (TGF -beta RII) mRNA. Compared with normal endothelium, TGF-beta(1) and TGF-beta (2) as well as TGF-beta RII, mRNA were upregulated in endothelium at the wo und edge. Injected recombinant soluble TGF-beta RII (TGF-beta R:Fc) localiz ed preferentially to the adventitia and developing neointima in the injured carotid artery, causing a reduction in intimal lesion formation (up to 65% ) and an increase in lumen area (up to 88%). The gain in lumen area was lar gely due to inhibition of negative remodeling, which coincided with reduced adventitial fibrosis and collagen deposition. Four days after injury, TGF- beta R:Fc treatment almost completely inhibited the induction of smooth mus cle alpha-actin expression in adventitial cells. In the vessel wall, TGF-be ta R:Fc caused a marked reduction in mRNA levels for collagens type I and I II. TGF-beta R:Fc had no effect on endothelial proliferation as determined by reendothelialization of the denuded rat aorta. Together, these findings identify the TGF-beta isoforms as major factors mediating adventitial fibro sis and negative remodeling after vascular injury, a major cause of resteno sis after angioplasty.