Plasminogen Activator Expression in Human Atherosclerotic Lesions

Abstract

The plasminogen activator (PA) system may participate in the pathogenesis of atherosclerosis by modulating the turnover of intimal fibrin and extracellular matrix deposits and by contributing to intimal cell migration. We present an analysis of tissue-type PA (tPA) and urokinase-type PA (uPA) expression at three levels: mRNA by in situ hybridization, antigen by immunohistochemistry, and enzymatic activity by histoenzymology 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 were detected in endothelial cells and smooth muscle cells (SMCs). In atherosclerotic arteries, tPA antigen and mRNA were increased in intimal SMCs and in macrophage-derived foam cells of fibro-fatty lesions. Part of the tPA was detected in the extracellular space and colocalized with fibrin deposits. uPA antigen and mRNA were detected in association with the intimal macrophages and SMCs. A particularly high uPA expression 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 lesions, whereas in normal arteries, only tPA-dependent activity was detected, mainly over the vasa vasorum. Also, strong tPA and uPA staining was detected in neomicrovessels of the plaques, suggesting that PAs may play a role in plaque angiogenesis. Our results suggest a local dynamic process of PA-dependent proteolysis in lesion areas that is associated with macrophages and SMCs. A better comprehension of these proteolytic mechanisms in advanced atherosclerotic plaques may provide the basis for therapeutic approaches for plaque stabilization.

Increased expression of urokinase during atherosclerotic lesion development causes arterial constriction and lumen loss, and accelerates lesion growth

“…These findings diminish enthusiasm for uPA gene therapy as a strategy for preventing intravascular thrombosis. Our study also suggests that uPA expression, which is elevated in atherosclerotic human arteries (5)(6)(7)(8), could contribute to the progression of human atherosclerosis. In the present study, uPA expression is increased in endothelium, whereas uPA is expressed predominantly by macrophages in more advanced human lesions (5).…”

“…uPA is expressed by endothelial cells and smooth muscle cells in normal human arteries (5). uPA expression is elevated in atherosclerotic human aortas, carotid arteries, and coronary arteries (5)(6)(7)(8), in which it is expressed by endothelial cells, smooth muscle cells, and macrophages (5). Elevated uPA expression could contribute to vascular lesion formation by facilitating smooth muscle cell migration and proliferation.…”

Prevention of Aneurysm Development and Rupture by Local Overexpression of Plasminogen Activator Inhibitor-1

“…In atherosclerotic plaques and arterial aneurysms, inflammation is thought to be associated with extracellular matrix lysis leading to thrombosis and arterial enlargement and either fibrous cap or arterial wall rupture. [39][40][41][42] Plasmin, u-PA, and t-PA have been detected in these arterial lesions, 43,44 as well as PAI-1. 45 In a model in mice, u-PA appears to be necessary for aneurysm formation.…”

Are we content with lowering blood pressure alone, or should we be asking something more from the antihypertensive drugs we use?: effects of antihypertensive agents on fibrinolytic function

“…Plasmin also activates transforming growth factorbeta, an anti-inflammatory cytokine that inhibits migration and proliferation of smooth muscle cells, being of crucial importance in the early stages of atherosclerosis. 3 Structural and functional changes in vascular endothelium, which could be interpreted as a response to injury to the cell, may be involved in the development of vascular disease.…”