REGULATION OF CELLULAR PROLIFERATION AND INTIMAL FORMATION FOLLOWING BALLOON INJURY IN ATHEROSCLEROTIC RABBIT ARTERIES

Injury to atherosclerotic arteries induces the expression of growth re gulatory genes that stimulate cellular proliferation and intimal forma tion, Intimal expansion has been reduced in vivo in nonatherosclerotic balloon-injured arteries by transfer of genes that inhibit cell proli feration, It is not known, however, whether vascular cell proliferatio n can be inhibited after injury in more extensively diseased atheroscl erotic arteries. Accordingly, the purpose of this study was to investi gate whether expression of recombinant genes in atherosclerotic arteri es after balloon injury could inhibit intimal cell proliferation, To t est this hypothesis, we examined the response to balloon injury in ath erosclerotic rabbit arteries after gene transfer of herpesvirus thymid ine kinase gene (tk) and administration of ganciclovir, Smooth muscle cells from hyperlipidemic rabbit arteries infected with adenoviral vec tors encoding tk were sensitive to ganciclovir, and bystander killing was observed in vitro. In atherosclerotic arteries, a human placental alkaline phosphatase reporter gene was expressed in intimal and medial smooth muscle cells and macrophages, identifying these cells as targe ts for gene transfer. Expression of tk in balloon-injured hyperlipidem ic rabbit arteries followed by ganciclovir treatment resulted in a 64% reduction in intimal cell proliferation 7 d after gene transfer (P = 0.004), and a 35-49% reduction in intimal area 21 d after gene transfe r, compared with five different control groups (P < 0.05), Replication of smooth muscle cells and macrophages was inhibited by tk expression and ganciclovir treatment, These findings indicate that transfer of a gene that inhibits cellular proliferation limits the intimal area in balloon-injured atherosclerotic arteries, Molecular approaches to the inhibition of cell proliferation in atherosclerotic arteries constitut e a possible treatment for vascular proliferative diseases.