Co-Localization of Fibrinolytic Activators and Inhibitors with Macrophages in Atherosclerotic Vessels

Abstract

The plasmin system is involved in hemostasis and tissue remodelling. The accumulation of plasminogen activators and their inhibitors in atherosclerotic lesions may be due to invasion of inflammatory cells in the vessel wall. High concentrations of macrophages are associated with increased risk of atherosclerotic plaque rupture. By immunohistochemistry on circumferential serial sections of atherosclerotic and healthy vessels the morphological association of plasminogen activators and inhibitors with macrophages was studied. Urokinase plasminogen activator (u-PA), plasminogen activator inhibitor type 2 (PAI-2), and macrophages were mainly expressed within plaques while tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were also expressed outside plaque lesions. Computer assisted image analysis on diseased vessels showed that regulatory proteins of the fibrinolytic system were found more often in areas positive for macrophages than in other parts of the sections ( p < 0.001). u-PA was significantly more defined to areas positive for macrophages than tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) ( p < 0.05). Similarly, PAI-2 expression was more associated with macrophage distribution than PAI-1 ( p < 0.05). Tumor necrosis factor α (TNFα), an inflammatoric mediator of macrophages, had the same levels of co-localization with macrophages as u-PA and PAI-2. These results suggest that u-PA and PAI-2 might be key factors for inflammatory regulation of plasmin mediated proteolysis in the vessel walls.