Plasminogen activator inhibitor-1 (PAI-1) plays a pivotal role in the regulation of the fibrinolytic system and in the modulation of extracellular proteolysis. Increased PAI-1 was found in atherosclerotic lesions and high PAI-1 plasma levels were associated with coronary heart disease. Smooth muscle cells (SMC) are a major source of PAI-1 within the vascular wall and PAI-1 was implicated in SMC migration, proliferation and apoptosis. We treated human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) with the glycoprotein 130 (gp130) ligands cardiotrophin-1 (CT-1), interleukin-6 (IL-6), leukemia inhibitory factor (LIF) or oncostatin M (OSM). Only OSM increased PAI-1 antigen and activity production significantly in these cells up to 20-fold. OSM upregulated mRNA specific for PAI-1 up to 4.5-fold in these cells. HCASMC and HASMC express gp130, OSM receptor, IL-6 receptor and LIF receptor. OSM induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylations HASMC. A PI3K inhibitor and a MEK inhibitor reduced Akt and ERK 1/2 phosphorylation, respectively and abolished OSM-induced PAI-1 upregulation. A JAK/STAT inhibitor, a p38 MAPK inhibitor or JNK inhibitor I did not inhibit the OSM-dependent PAI-1 induction. OSM enhanced proliferation of both HCASMC and HASMC by 77% and 90%, respectively. We hypothesize that if the effect of OSM on PAI-1 expression in smooth muscle cells is operative in vivo it could- via modulation of fibrinolysis and extracellular proteolysis, be involved in the development of vascular pathologies such as plaque progression, destabilization and subsequent thrombus formation, and restenosis and neointima formation.