THE ROLE OF PLASMINOGEN ACTIVATORS IN THE DEVELOPMENT OF ATHEROSCLEROTIC AND RESTENOTIC LESIONS

The plasminogen activator (PA) system may participate in the pathogene sis of atherosclerosis and of restenosis after angioplasty by modulati ng the turnover of intimal fibrin and extracellular matrix deposits an d by contributing to intimal cell migration. This paper summarise our results on the expression of tissue-type PA (t-PA), urokinase (u-PA), u-PA receptor (uPAR) and PAI-1 in atherosclerotic and restenotic lesio ns. In atherosclerotic arteries, t-PA, u-PA and PAI-1 were found in in timal smooth muscle cells (SMC) and macrophage-derived foam cells. A p articularly high u-PA expression was noted on macrophages localised on the rims of the necrotic core. u-PA-dependent lytic activity was dete cted in macrophage rich areas of the advanced lesions. The similar dis tribution pattern of PAI-1 suggests its possible counterbalancing role in the local modulation PA dependent proteolysis within lesions. Time -course analysis of expression of PAs after balloon injury of rat and rabbit arteries have revealed that t-PA and PAI-1 antigen and mRNA are overexpressed by some SMC scattered in the subintimal area after 1-3 days following balloon injury. The neointimal SMC detected after 9 day s have exhibited a strong expression of t-PA, PAI-1, u-PA and uPAR ant igen and mRNA. PA dependent proteolytic activity was found in the neoi ntimal area, especially after 14 days and it was inhibited in a large extent by anti t-PA antibodies, These results support the existence of a local dynamic process of PA dependent proteolysis in association wi th the advanced atherosclerotic plaque and with the hyperproliferative response of the SMC of injured arteries.