Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries

Abstract

Though the efficacy of intravascular gene transfer has been demonstrated in native vessels following acute injury, this methodology has not been validated in complex models of vascular injury that more closely mimic clinical angioplasty procedures. Previous studies have shown that Gax gene overexpression modulates the injury-induced remodeling of the vessel in rat carotid and normal rabbit iliac arteries. Here, we evaluated the effect of the Gax gene delivery in atheromatous stented vessels. Rabbits were fed 120 g daily of 1% cholesterol diet for 3 weeks. At 1 week they underwent initial injury on the external iliac artery, then balloon angioplasty was performed at 3 weeks at the same site with a 2.5 mm diameter channel balloon catheter (three times 1 min at 6 atm). Either saline (n = 4) or the control viral construct Ad-CMVluc (5 x 109 p.f.u.) (n = 5) or Ad-CMVGax (5 x 10(9) p.f.u.) (n = 4) was delivered with a poloxamer mixture via a channel balloon (6 atm, 30 min), and a 15 mm long Palmaz-Schatz stent (PS154) was then deployed at the site (1 min, 8 atm). Arteries were analyzed 1 month later. At 1 month, the Ad-CMVGax treated arteries exhibited a lower maximal intimal area (1. 15+/-0.1 mm2) than saline (1.87+/-0.15 mm2, P = 0.007) or Ad-CMVluc-treated vessels (1.98+/-0.31 mm2, P = 0.04). Likewise Ad-CMVGax-treated vessels displayed a lower maximal percentage cross-sectional area narrowing (35.1+/-3.5%) than saline (65.3+/-9.4%, P = 0.01) or Ad-CMVluc-treated vessels (62.7+/-6.7%, P = 0.02). Angiographic analysis revealed larger minimal lumen diameter in Ad-CMVGax treated arteries (2.0+/-0.1 mm) than saline (1.14+/-0.36 mm, P = 0.06) or Ad-CMVluc-treated vessels (1.23+/-0.25 mm, P = 0.02). Overexpression of the Gax gene inhibits neointimal hyperplasia and lumen loss in atheromatous stented rabbit iliac arteries.