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

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 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-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.