Abstract
Activation of platelets leads to thrombosis and secretion of PDGF and other stimulators of smooth muscle cell (SMC) migration/proliferation, resulting in neointima formation. RGD-containing peptides can prevent the binding of several integrins including αIIb/β3 (GP II b/ III a) in platelet aggregation and αv/β3 in smooth muscle cell migration, both of which are involved in neointima formation. Thrombus formation was measured by transillumination and image analysis at 30 min, 24 hr and 72 hr after vascular injury and neointima was quantified in the same carotid arteries in hamsters at 2 weeks. The proliferation index of SMC was determined at 1, 3, 5, 7, and 14 days after denudation following four injections of BrdU. After treatment with G4120 at a dose of 100 μg/kg/hr, both thrombus size (89.2 ± 5.5% inhibition vs control) and neointima formation (60.2 ± 6.6% inhibition vs control) were significantlly reduced. Pooling individual data for treated hamsters with those obtained for the untreated animals still resulted in a significant correlation (r=0.64, n=47, P < 0.001). Reduction of neointima by G4120 is linked to a lower percentage of proliferating cells in the media and neointima from 16.5 ± 9.7% on day 1 (media) and 20.2 ± 7.3% on day 5 (intima) in the control animals to 9.9 ± 6.1% on day 1 (media) and 13.4 ± 9.0 on day 5 (intima) in the G4120 treated animals. In conclusion, inhibition of integrin function results in reductions of thrombus and neointima formations. This effect is due both an early event, which is caused by inhibition of PDGF secretion by platelets with blocked α Ilb/β3, and to a late event, possibly by interference with SMC αv/β3.
