YD-3 is a PAR4 antagonist that significantly inhibits thrombin-induced platelet aggregation in rabbits (IC(50)=28.3 microM). In addition, YD-3 suppresses thrombin-induced proliferation of vascular smooth muscle cells (VSMCs) and reduces neointimal thickening after balloon injury. Through Ras- and ERK1/2-mediated signaling pathways, YD-3 impedes thrombin-driven VSMC proliferation. When analyzed with Western blot, YD-3 primarily inhibits thrombin-induced expression of vascular endothelial growth factor receptor 2 (Flk-1) without affecting extracellular signal-regulated kinase 1/2 phosphorylation. YD-3 could potentially have value in elucidating the pathophysiology of thrombin-induced angiogenesis.