Document Detail

Adenovirus-mediated gene transfer of transforming growth factor-beta3, but not transforming growth factor-beta1, inhibits constrictive remodeling and reduces luminal loss after coronary angioplasty.
MedLine Citation:
PMID:  14638551     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Extracellular matrix (ECM) remodeling is central to the development of restenosis after PTCA. Substantial evidence implicates transforming growth factor-beta1 (TGF-beta1), a regulator of ECM deposition by vascular cells, in its pathogenesis. TGF-beta3 reduces TGF-beta1-induced ECM deposition in cutaneous wounds. We therefore investigated the effects of intracoronary expression of TGF-beta3 and TGF-beta1 on luminal loss after angioplasty. METHODS AND RESULTS: Porcine coronary arteries received an adenovirus expressing TGF-beta3, TGF-beta1, or lacZ (beta-galactosidase), or PBS only, at the site of angioplasty. Morphometric analysis 28 days after angioplasty confirmed reduced luminal loss in TGF-beta3 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-beta1 vessels (-1.02+/-0.19 mm2; P=0.48). An increase in the external elastic lamina area in TGF-beta3-treated vessels (+0.73+/-0.32 mm2) contrasted with decreases in control vessels (mean, -0.53+/-0.17 mm2; P=0.001) and TGF-beta1 vessels (-0.87+/-0.34 mm2; P=0.003). Collagen content increased at the site of injury in TGF-beta3-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-beta1-treated vessels. CONCLUSIONS: Expression of TGF-beta3 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.
Paul A Kingston; Sanjay Sinha; Clare E Appleby; Anne David; Thomas Verakis; Maria G Castro; Pedro R Lowenstein; Anthony M Heagerty
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-11-24
Journal Detail:
Title:  Circulation     Volume:  108     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-05     Completed Date:  2004-01-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2819-25     Citation Subset:  AIM; IM    
Vascular Gene Therapy Unit, University of Manchester, Manchester, UK.
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MeSH Terms
Adenoviridae / genetics*
Angioplasty, Transluminal, Percutaneous Coronary / adverse effects*
Cells, Cultured
Collagen / metabolism
Coronary Vessels / drug effects,  metabolism
Epithelial Cells / cytology,  drug effects,  metabolism
Gene Expression
Gene Transfer Techniques
Muscle, Smooth, Vascular / cytology,  drug effects,  metabolism
Transforming Growth Factor beta / genetics,  metabolism*,  pharmacology
Transforming Growth Factor beta1
Transforming Growth Factor beta3
Tunica Intima / metabolism,  pathology
Reg. No./Substance:
0/Transforming Growth Factor beta; 0/Transforming Growth Factor beta1; 0/Transforming Growth Factor beta3; 9007-34-5/Collagen

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