The role of plasminogen activators in the development of atherosclerotic and restenotic lesions

Abstract

The plasminogen activator (PA) system may participate in the pathogenesis of atherosclerosis and of restenosis after angioplasty by modulating the turnover of intimal fibrin and extracellular matrix deposits and 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 lesions. In atherosclerotic arteries, t-PA, u-PA and PAI-1 were found in intimal smooth muscle cells (SMC) and macrophage-derived foam cells. A particularly high u-PA expression was noted on macrophages localised on the rims of the necrotic core. u-PA-dependent lytic activity was detected in macrophage rich areas of the advanced lesions. The similar distribution 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 days have exhibited a strong expression of t-PA, PAI-1, u-PA and uPAR antigen and mRNA. PA dependent proteolytic activity was found in the neointimal 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 with the advanced atherosclerotic plaque and with the hyperproliferative response of the SMC of injured arteries..