doi: 10.1161/hc4601.099405
(Circulation. 2001;104:2595.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-ß Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition
From the Molecular Medicine and Gene Therapy Unit, University of Manchester (P.A.K., A.D., M.G.C., P.R.L.), and Department of Medicine, Manchester Royal Infirmary (S.S., A.M.H.), Manchester, UK.
Correspondence to Prof Anthony M. Heagerty, Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. E-mail heagerty{at}fs1.cmht.nwest.nhs.uk
Background Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-ß1 (TGF-ß1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-ß1 on luminal loss after PTCA.
Methods and Results Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-ß type II receptor (Ad5-RIIs), an adenovirus expressing ß-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs–injected arteries (1.71±0.12 mm2) than in the Ad5-lacZ (1.33±0.13 mm2) or vehicle-only (1.08±0.17 mm2; P=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (P=0.013) and external (P=0.031) elastic laminae in Ad5-RIIs–treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (P=0.004).
Conclusions Adenovirus-mediated antagonism of TGF-ß1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-ß1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy–mediated antagonism of TGF-ß1 as prophylactic therapy for restenosis.
Key Words: angioplasty • gene therapy • restenosis • collagen
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