Selective tyrosine kinase inhibitor for the platelet-derived growth factorreceptor in vitro inhibits smooth muscle cell proliferation after reinjuryof arterial intima in vivo

The long-term success of coronary angioplasty is limited by restonosis. Thi s study was undertaken to investigate whether and to what extent the enhanc ed proliferative response observed in a balloon reinjury model of rat aorta is regulated by the PDGF receptor (PDGF-R). Balloon injury was performed t o 14-day-old pre-existing neointimal lesion in rat aorta. PDGF receptor and ligand immunoreactivity were measured at several time points after the fir st and second injury, and PDGF-R signaling was blocked with a selective inh ibitor of PDGF-R tyrosine kinase. In the neointima, after repeated injury, upregulation of PDGF-AA was seen to coincide with a prompt proliferative re sponse of smooth muscle cells (SMC). Administration of the PDGF-R tyrosine kinase inhibitor in vivo, tested and found to inhibit the proliferation of SMC induced by PDGF-AA and PDGF-BB, but not by IGF-1, EGF, or bFGF, resulte d in a 60% reduction in the absolute number and percentage of BrdU+ cells a fter the second balloon injury to pre-existing neointima, but had no signif icant effect on proliferation after the first injury. Endpoint lesion are w as reduced by 50% in the treated group at 14 days after the second injury. The results suggest that systemic administration of a tyrosine kinase inhib itor specific for the PDGF-R can be useful in the prevention of restenosis.