Angiogenic therapy for the chronically ischemic lower limb in a rabbit model

The purpose of this study was to evaluate the longterm effectiveness of bas ic fibroblast growth factor (bFGF) in achieving neovascularization followin g ischemia from arterial ligation and to determine an optimal dosage level. We used an Ameroid constrictor to produce progressive occlusion of the lef t femoral artery of rabbits. At 2 weeks, the rabbits were randomized to rec eive intravenous injection of vehicle (group A, n = 15); 3 mug/kg/day bFGF (group B, n = 12); 10 mug/kg/day bFGF (group C, n = 12); or 16 mug/kg/day b FGF (group D, n = 15) for 3 days, At 1 to 37 days after surgery, we assesse d limb neovascularization by transcutaneous oximetry (TCPO2), angiography, heart rate, arterial pressure, peripheral vascular resistance (PRU), and mu scle blood flow (MBF) during steady-state intra-arterial infusion of saline (basal), acetylcholine, papaverine, or serotonin under anesthesia and capi llary density (cap/mm(2)) and capillary per muscle fiber ratio (cap/F). Gro ups B and C showed significantly greater change in TCPO2, over time than gr oups A and D (P < 0.0001), Group D showed the lowest TCPO2, values from day s 14 to 37 and group C the highest. Groups B and C showed a higher number o f vessels filled with contrast agent than groups A and D (P < 0.0001), Calf cap/mm(2) and cap/F were significantly higher in groups B and C than group s A and D (P < 0.0001). Calf basal MBF values were higher in groups B and C than in groups A and D, but were not statistically significant. Group D sh owed the highest level in basal PRU, There were no significant differences in heart rate or blood pressure among the groups. These results show (1) tr eatment with bFGF has no adverse hemodynamic effects, (2) bFGF enhances ang iogenesis and circulation at moderate doses, and these effects persist at l east several weeks, and (3) high doses of bFGF may inhibit angiogenesis and collateralcirculation. (C) 2000 Academic Press.