INHIBITION OF PLATELET-DERIVED GROWTH-FACTOR RECEPTOR TYROSINE KINASEINHIBITS VASCULAR SMOOTH-MUSCLE CELL-MIGRATION AND PROLIFERATION

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) h ave been linked to vascular smooth muscle cell (SMC) migration and pro liferation leading to atherosclerosis, restenosis, and chronic allogra ft rejection. This study describes the effect of CGP 53716, a specific PDGFR tyrosine kinase inhibitor on SMC proliferation and migration in vitro and in neointimal formation in vivo. CGP 53716 inhibited dose d ependently tyrosine phosphorylation of both the known PDGFRs: the PDGF R-alpha and PDGFR-beta. In primary rat SMC cultures, a dose-dependent inhibition of PDGF-AA and PDGF-BB induced migration, and tritiated thy midine incorporation of SMC was seen at nontoxic concentrations. After rat carotid artery ballooning injury in vivo, the migration of alpha- actin-positive cells on the luminal side of internal elastic lamina wa s decreased with 50 mg.kg(-1).day(-1) of CGP 53716 from 38 +/- 10 (con trol group) to 4 +/- 2 (P < 0.0001, Mann-Whitney U test, N = 18). CGP 53716 did not inhibit the number of replicating bromodeoxyuridine (Brd U)-incorporating cells in the intima, media, or adventitia during BrdU labeling at 0-96 postoperative h, though it inhibited significantly ( P < 0.01) the replication of medial and intimal cells from 93 h onward . Intima/ media ratio was inhibited by 40% after 14 days in the CGP 53 716-treated group (P = 0.028) after rat aortic denudation. The results indicate that inhibition of the PDGFR tyrosine kinase inhibits SMC mi gration and proliferation in vitro, SMC migration, and, to a lesser ex tent, proliferation after ballooning injury in vivo, confirming a caus al role for activation of the PDGFR and the formation of neointimal le sions.