Soluble Transforming Growth Factor-β Type II Receptor Inhibits Negative Remodeling, Fibroblast Transdifferentiation, and Intimal Lesion Formation But Not Endothelial Growth

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Abstract
—Using the rat balloon catheter denudation model, we examined the role of transforming growth factor-β (TGF-β) isoforms in vascular repair processes. By en face in situ hybridization, proliferating and quiescent smooth muscle cells in denuded vessels expressed high levels of mRNA for TGF-β 1 , TGF-β 2 , TGF-β 3 , and lower levels of TGF-β receptor II (TGF-βRII) mRNA. Compared with normal endothelium, TGF-β 1 and TGF-β 2 , as well as TGF-βRII, mRNA were upregulated in endothelium at the wound edge. Injected recombinant soluble TGF-βRII (TGF-βR:Fc) localized 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 largely due to inhibition of negative remodeling, which coincided with reduced adventitial fibrosis and collagen deposition. Four days after injury, TGF-βR:Fc treatment almost completely inhibited the induction of smooth muscle α-actin expression in adventitial cells. In the vessel wall, TGF-βR:Fc caused a marked reduction in mRNA levels for collagens type I and III. TGF-βR:Fc had no effect on endothelial proliferation as determined by reendothelialization of the denuded rat aorta. Together, these findings identify the TGF-β isoforms as major factors mediating adventitial fibrosis and negative remodeling after vascular injury, a major cause of restenosis after angioplasty.

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