title: Soluble transforming growth factor-beta type II receptor inhibits negative remodeling, fibroblast transdifferentiation, and intimal lesion formation but not endothelial growth.
abstract: Using the rat balloon catheter denudation model, we examined the role of transforming growth factor-beta (TGF-beta) 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-beta1, TGF-beta2, TGF-beta3, and lower levels of TGF-beta receptor II (TGF-betaRII) mRNA. Compared with normal endothelium, TGF-beta1 and TGF-beta2, as well as TGF-betaRII, mRNA were upregulated in endothelium at the wound edge. Injected recombinant soluble TGF-betaRII (TGF-betaR: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-betaR:Fc treatment almost completely inhibited the induction of smooth muscle alpha-actin expression in adventitial cells. In the vessel wall, TGF-betaR:Fc caused a marked reduction in mRNA levels for collagens type I and III. TGF-betaR: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 fibrosis and negative remodeling after vascular injury, a major cause of restenosis after angioplasty.
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, South Portland, ME 04106, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Smith
authors.forename: S R
authors.initials: SR
authors.lastname: Bryant
authors.forename: L L
authors.initials: LL
authors.lastname: Couper
authors.forename: C P
authors.initials: CP
authors.lastname: Vary
authors.forename: P J
authors.initials: PJ
authors.lastname: Gotwals
authors.forename: V E
authors.initials: VE
authors.lastname: Koteliansky
authors.forename: V
authors.initials: V
authors.lastname: Lindner
mesh_terms: D000199:Actins / Q000378:metabolism; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000166:cytology; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology; D020212:Carotid Artery Injuries; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000293:injuries* / Q000473:pathology; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006965:Hyperplasia; D017403:In Situ Hybridization; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017539:Tunica Intima / Q000737:chemistry / Q000166:cytology / Q000201:enzymology
chemical_list: D000199:Actins; D008024:Ligands; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II