ANTISENSE BASIC FIBROBLAST GROWTH-FACTOR GENE-TRANSFER REDUCES EARLY INTIMAL THICKENING IN A RABBIT FEMORAL-ARTERY BALLOON INJURY MODEL

Purpose: The purpose of this study was to determine whether endogenous basic fibroblast growth factor (bFGF) production contributes to the i ntimal hyperplastic response to injury in a model of rabbit femoral ar tery balloon injury. Inhibition of de novo production of bFGF protein was targeted by intramural adenoviral gene transfer of antisense bFGF (Ad.ASbFGF) RNA. The adenovirus was delivered locally intraluminally a t the time of arterial injury. Methods: New Zealand White rabbits unde rwent balloon injury of the superficial femoral artery, followed by in traluminal delivery of an adenoviral vector encoding a rat antisense b FGF (ASbFGF) transcript at a concentration of 1 X 10(10) plaque-formin g units per milliliter. Control animals were treated in a similar fash ion, using either an adenovirus encoding the lac reporter gene (Ad.lac Z) or phosphate-buffered saline solution (PBS; vehicle) alone. Two wee ks after balloon injury, rabbits were killed and perfusion fixed. Femo ral arteries were harvested for histomorphometric analysis. Intimal an d medial wall thickness was measured at eight points around the vessel perimeter, and mean intimal/medial (I/M) thickness ratios were compar ed by analysis of variance and Student's t test. In addition, medial c ell proliferation in Ad.ASbFGF and Ad.lacZ treated arteries was evalua ted 4 days and 2 weeks after balloon injury by 5-Bromo-2'-deoxyuridine labeling. Results: At 14 days (n = 25) after balloon injury, histomor phometric analysis revealed a significant inhibition of intimal thicke ning in Ad.ASbFGF-treated arteries as compared with Ad.lacZ-treated an d PBS-treated controls (I/M thickness ratios +/- SD, 0.43 +/- 0.22 for Ad.ASbFGF vs 1.03 +/- 0.28 for Ad.lacZ and 0.86 +/- 0.19 for PBS; p < 0.0001 and p = 0.004, respectively). There was no significant differe nce in the I/M thickness ratios of Ad.lacZ-treated and IFS-treated ves sels (P = 0.27). Although there was no significant difference in the p roliferation index of Ad.ASbFGF-treated and Ad.lacZ-treated vessels 4 days after injury, an increase in apoptosis was noted in the Ad.ASbFGF -treated vessels 4 days after balloon injury. Conclusions: The use of ASbFGF RNA gene transfer, designed to inhibit de novo bFGF synthesis a fter balloon injury, results in a significant inhibition of neointimal formation. This suggests that continued bFGF synthesis contributes to the arterial response to injury in rabbits. ASbFGF gene transfer may be an effective strategy in limiting the intimal hyperplastic response after vascular reconstructive procedures.