Published Online
on November 24, 2003

A more recent version of this article appeared on December 2, 2003

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Submitted on April 18, 2002
Revised on June 23, 2003
Accepted on August 1, 2003

Adenovirus-Mediated Gene Transfer of Transforming Growth Factor-₃, but Not Transforming Growth Factor-₁, Inhibits Constrictive Remodeling and Reduces Luminal Loss After Coronary Angioplasty

Paul A. Kingston MRCP, PhD^*, Sanjay Sinha MRCP, PhD, Clare E. Appleby BA, MRCP, Anne David PhD, Thomas Verakis MSc, Maria G. Castro PhD, Pedro R. Lowenstein MD, PhD, and Anthony M. Heagerty FRCP, MD

From the Vascular Gene Therapy Unit, University of Manchester (P.A.K., A.D., C.E.A., T.V., M.G.C., P.R.L.), and Department of Medicine, Manchester Royal Infirmary (S.S., A.M.H.), Manchester, UK. Drs Castro and Lowenstein are now with the Gene Therapeutics Research Institute, Cedars Sinai Medical Center, Los Angeles, Calif.

^* To whom correspondence should be addressed. E-mail: paul.a.kingston{at}man.ac.uk.

Background--Extracellular matrix (ECM) remodeling is central to the development of restenosis after PTCA. Substantial evidence implicates transforming growth factor-₁ (TGF-₁), a regulator of ECM deposition by vascular cells, in its pathogenesis. TGF-₃ reduces TGF-₁--induced ECM deposition in cutaneous wounds. We therefore investigated the effects of intracoronary expression of TGF-₃ and TGF-₁ on luminal loss after angioplasty.

Methods and Results--Porcine coronary arteries received an adenovirus expressing TGF-₃, TGF-₁, or lacZ (-galactosidase), or PBS only, at the site of angioplasty. Morphometric analysis 28 days after angioplasty confirmed reduced luminal loss in TGF-₃ vessels (-0.65±0.10 mm²) compared with lacZ (-1.18±0.19 mm²) or PBS only (-1.19±0.17 mm²; P=0.003). Luminal loss was not reduced in TGF-₁ vessels (-1.02±0.19 mm²; P=0.48). An increase in the external elastic lamina area in TGF-₃-treated vessels (+0.73±0.32 mm²) contrasted with decreases in control vessels (mean, -0.53±0.17 mm²; P=0.001) and TGF-₁ vessels (-0.87±0.34 mm²; P=0.003). Collagen content increased at the site of injury in TGF-₃-treated vessels (26.1±14.2%) but decreased in the lacZ (-22.8±6.6%) and PBS-only (-23.4±7.0%; P=0.002) groups and was not significantly changed in TGF-₁-treated vessels.

Conclusions--Expression of TGF-₃ inhibits constrictive remodeling after PTCA and reduces luminal loss. This is accompanied by increased adventitial collagen, which may act as an external "scaffold" preventing vessel constriction. These findings confirm the potential of gene therapies that modify ECM remodeling for prophylaxis of restenosis.

Key words: angioplasty • gene therapy • restenosis • collagen

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