A MODEL OF ARTERIAL SMOOTH MUSCLE CELL PROLIFERATION TO STUDY RESTENOSIS

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Recently, considerable interest has focused on the vascular smooth muscle cell (SMC) response to injury, particularly as it relates to restenosis following angioplasty. We have developed an experimental model of arterial SMC proliferation, mimicking restenosis, in the normocholesterolemic rabbit. We have found that crush injury to the central artery of the rabbit ear causes histologic changes morphologically similar to that of restenosis, and we have characterized previously the natural history of such a lesion. Using this model, we have examined the effects of a chimeric fusion toxin in vivo. Acidic FGF-PE664Glu KDEL (aFGF-PE) is a fusion protein generated by ligating the genes encoding acidic fibroblast growth factor (FGF) with Pseudomonas exotoxin. The exotoxin is mutated to render its binding domain non-functional, and the fusion protein is expressed in E. coli. This chimeric toxin targets tumor cells and SMC's bearing the FGF receptor in vitro, and has potent cytotoxic effects. To determine if aFGF-PE inhibits SMC proliferation in response to injury in vivo, we studied neointimal formation following arterial crush injury in normocholesterolemic rabbits. New Zealand White rabbits underwent crush injury to the central auricular artery. Rabbits received aFGF-PE (10 or 30 microg/ear, N=31) or placebo (N=17), as one hour intra-arterial infusions, 1, 3, 6, and 9 days after injury. Rabbits were sacrificed on day 14, and each lesion was planimeterized. Neointimal formation was equivalent in the 10 and 30 microg groups. Mean neointimal area, expressed as a percentage of the area of the tunica media, was 35+/-19% in treated rabbits vs. 53+/-37% in controls (mean +/- SD, p=0.05). We conclude that local administration of aFGF-PE inhibits neointimal formation following primary arterial injury in rabbits. Further studies will be necessary to determine whether these results can be extrapolated to other animal models. Further studies will be necessary to determine whether aFGF-PE will exert a salutary effect when given systemically, and when arterial injury is superimposed on an underlying arteriosclerotic lesion.