© 1999 American Heart Association, Inc.
Original Contribution |
Soluble Transforming Growth Factor-ß Type II Receptor Inhibits Negative Remodeling, Fibroblast Transdifferentiation, and Intimal Lesion Formation But Not Endothelial Growth
From the Center for Molecular Medicine (J.D.S., S.R.B., L.L.C., C.P.H.V., V.L.), Maine Medical Center Research Institute, South Portland, Me, and Biogen, Inc (P.J.G., V.E.K.), Cambridge, Mass.
Correspondence to Volkhard Lindner, Center for Molecular Medicine, Maine Medical Center Research Institute, 125 John Roberts Rd, Suite 12, South Portland, ME 04106. E-mail lindnv{at}poa.mmc.org
Abstract—Using the rat balloon
catheter denudation model, we examined the role of transforming growth
factor-ß (TGF-ß) 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-ß1, TGF-ß2, TGF-ß3, and
lower levels of TGF-ß receptor II (TGF-ßRII) mRNA. Compared with
normal endothelium, TGF-ß1 and
TGF-ß2, as well as TGF-ßRII, mRNA were upregulated in
endothelium at the wound edge. Injected recombinant
soluble TGF-ßRII (TGF-ßR: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-ßR:Fc treatment almost completely inhibited the induction
of smooth muscle 
-actin expression in adventitial cells. In the
vessel wall, TGF-ßR:Fc caused a marked reduction in mRNA levels for
collagens type I and III. TGF-ßR:Fc had no effect on
endothelial proliferation as determined by
reendothelialization of the denuded rat aorta.
Together, these findings identify the TGF-ß isoforms as major factors
mediating adventitial fibrosis and negative remodeling after vascular
injury, a major cause of restenosis after angioplasty.
Key Words: intimal hyperplasia • collagen • fibrosis • smooth muscle -actin • myofibroblast
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