TISSUE-TYPE PLASMINOGEN-ACTIVATOR IS A POTENT MITOGEN FOR HUMAN AORTIC SMOOTH-MUSCLE CELLS

Tissue-type plasminogen activator (t-PA) is a potent and efficacious m itogen for growth-arrested cultured human aortic smooth muscle cells, stimulating an increase in cell number at 0.3-30 nM concentration. Dou ble-chain t-PA is as efficient as single-chain t-PA in stimulating smo oth muscle cell mitogenesis, whereas single-chain urokinase-type plasm inogen activator (u-PA) or u-PA and plasmin or plasminogen are ineffec tive. Plasminogen activator inhibitor-1, Pefabloc-TPA, diisopropyl flu orophosphate or alpha1-anti-trypsin inhibit the mitogenic effect of t- PA for smooth muscle cells in a dose-dependent manner, showing that it is dependent on the enzymatic activity. t-PA activated phosphoinositi de turnover in smooth muscle cells through a pertussis toxin-insensiti ve pathway and stimulated proto-oncogene c-fos and c-jun mRNA levels. These findings indicate that t-PA stimulates vascular human smooth mus cle cell proliferation and suggest for the first time that it may cont ribute to intimal smooth muscle cell proliferation after vascular inju ry as a result of angioplasty or vascular compromise during atherogene sis.