Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-β Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition

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Abstract
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-β1 (TGF-β1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-β1 on luminal loss after PTCA. Methods and Results Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-β type II receptor (Ad5-RIIs), an adenovirus expressing β-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 mm 2 ) than in the Ad5- lacZ (1.33±0.13 mm 2 ) or vehicle-only (1.08±0.17 mm 2 ; 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-β1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-β1 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-β1 as prophylactic therapy for restenosis.