This Article Full Text Full Text (PDF) All Versions of this Article: 108/22/2819    most recent 01.CIR.0000097068.49080.A0v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kingston, P. A. Articles by Heagerty, A. M. Search for Related Content PubMed PubMed Citation Articles by Kingston, P. A. Articles by Heagerty, A. M. Related Collections Restenosis Growth factors/cytokines Catheter-based coronary and valvular interventions: other Gene therapy

(Circulation. 2003;108:2819.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Adenovirus-Mediated Gene Transfer of Transforming Growth Factor-ß₃, but Not Transforming Growth Factor-ß₁, 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; 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.

Correspondence to Dr Paul Kingston, Room 1.302, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. E-mail paul.a.kingston{at}man.ac.uk

Received April 18, 2002; de novo received June 23, 2003; de novo received July 31, 2002; accepted August 1, 2003.

Background— Extracellular matrix (ECM) remodeling is central to the development of restenosis after PTCA. Substantial evidence implicates transforming growth factor-ß₁ (TGF-ß₁), a regulator of ECM deposition by vascular cells, in its pathogenesis. TGF-ß₃ reduces TGF-ß₁—induced ECM deposition in cutaneous wounds. We therefore investigated the effects of intracoronary expression of TGF-ß₃ and TGF-ß₁ on luminal loss after angioplasty.

Methods and Results— Porcine coronary arteries received an adenovirus expressing TGF-ß₃, TGF-ß₁, or lacZ (ß-galactosidase), or PBS only, at the site of angioplasty. Morphometric analysis 28 days after angioplasty confirmed reduced luminal loss in TGF-ß₃ 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-ß₁ vessels (-1.02±0.19 mm²; P=0.48). An increase in the external elastic lamina area in TGF-ß₃–treated vessels (+0.73±0.32 mm²) contrasted with decreases in control vessels (mean, -0.53±0.17 mm²; P=0.001) and TGF-ß₁ vessels (-0.87±0.34 mm²; P=0.003). Collagen content increased at the site of injury in TGF-ß₃–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-ß₁–treated vessels.

Conclusions— Expression of TGF-ß₃ 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

This article has been cited by other articles:

				R. Kundi, S. T. Hollenbeck, D. Yamanouchi, B. C. Herman, R. Edlin, E. J. Ryer, C. Wang, S. Tsai, B. Liu, and K. C. Kent Arterial gene transfer of the TGF-{beta} signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF Cardiovasc Res, November 1, 2009; 84(2): 326 - 335. [Abstract] [Full Text] [PDF]

				B. S. Fleenor and D. K. Bowles Exercise training decreases the size and alters the composition of the neointima in a porcine model of percutaneous transluminal coronary angioplasty (PTCA) J Appl Physiol, September 1, 2009; 107(3): 937 - 945. [Abstract] [Full Text] [PDF]

				Z. Jiang, P. Yu, M. Tao, C. Fernandez, C. Ifantides, O. Moloye, G. S. Schultz, C. K. Ozaki, and S. A. Berceli TGF-beta- and CTGF-mediated fibroblast recruitment influences early outward vein graft remodeling Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H482 - H488. [Abstract] [Full Text] [PDF]

				R. Khan, A. Agrotis, and A. Bobik Understanding the role of transforming growth factor-{beta}1 in intimal thickening after vascular injury Cardiovasc Res, May 1, 2007; 74(2): 223 - 234. [Abstract] [Full Text] [PDF]

				J. P.G. Sluijter, R. E. Verloop, W. P.C. Pulskens, E. Velema, J. M. Grimbergen, P. H. Quax, M.-J. Goumans, G. Pasterkamp, and D. P.V. de Kleijn Involvement of furin-like proprotein convertases in the arterial response to injury Cardiovasc Res, October 1, 2005; 68(1): 136 - 143. [Abstract] [Full Text] [PDF]