PLASMINOGEN-ACTIVATOR EXPRESSION IN HUMAN ATHEROSCLEROTIC LESIONS

The plasminogen activator (PA) system may participate in the pathogene sis of atherosclerosis by modulating the turnover of intimal fibrin an d extracellular matrix deposits and by contributing to intimal cell mi gration. We present an analysis of tissue-type PA (tPA) and urokinase- type PA (uPA) expression at three levels: mRNA by in situ hybridizatio n, antigen by immunohistochemistry, and enzymatic activity by histoenz ymology and zymography. For PA colocalization with cellular or matrix components, we used double immunofluorescence labeling in conjunction with confocal microscopy. In normal arteries, tPA antigen and mRNA wer e detected in endothelial cells and smooth muscle cells (SMCs). In ath erosclerotic arteries, tPA antigen and mRNA were increased in intimal SMCs and in macrophage-derived foam cells of fibrofatty lesions. Part of the tPA was detected in the extracellular space and colocalized wit h fibrin deposits. uPA antigen and mRNA were detected in association w ith the intimal macrophages and SMCs. A particularly high uPA expressi on was noted on macrophages localized on the rims of the necrotic core . Moreover, using a novel histoenzymological assay as well as classic zymography, we revealed uPA-dependent lytic activity in the advanced l esions, whereas in normal arteries, only tPA-dependent activity was de tected, mainly over the vasa vasorum. Also, strong tPA and uPA stainin g was detected in neomicrovessels of the plaques, suggesting that PAs may play a role in plaque angiogenesis. Our results suggest a local dy namic process of PA-dependent proteolysis in lesion areas that is asso ciated with macrophages and SMCs. A better comprehension of these prot eolytic mechanisms in advanced atherosclerotic plaques may provide the basis for therapeutic approaches for plaque stabilization.