Atherosclerosis and fibrinolysis. A study in human blood vessels

Abstract

Atherosclerosis is a major cause of morbidity and mortality. The fibrinolytic system may be involved with several aspects of human atherosclerotic disease by regulating cellular migration, matrix remodelling and local thrombogenicity. The aim of the present investigation was to test the hypotheses: -Local expression of fibrinolytic factors is determined by inflammatory activity.-Macrophages and fibrinolytic factors are heterogeneously distributed in human atherosclerotic vessels.-Fibrinolytic factors are altered in aneurysmatic arteries. Immunohistochemistry was used to characterise the distribution of tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), plasminogen activator inhibitors type 1 and 2 (PAI-1 and PAI-2), tumour necrosis factor alpha (TNF), tissue factor (TF) and macrophages in vascular sections from patients with peripheral atherosclerotic disease. Co-localisation of fibrinolytic factors with macrophages was calculated using computer assisted image analysis of circumferential serial sections. Heterogeneity was evaluated by calculating the representativity of random samples concerning the expression of antigens as a function of sample size. Tissue extraction and immunosorbant assay was used to compare antigen and activity levels of fibrinolytic factors in aneurysmatic versus normal aortic tissue. The expression of fibrinolytic factors, especially u-PA and PAI-2, was different in atherosclerotic vessels compared to healthy controls and clearly related to the presence of macrophages. u-PA co-localised with an activated subpopulation of macrophages. Macrophages, fibrinolytic factors, TNF and TF were heterogeneously distributed in atherosclerotic vessels and the representativity of small vascular samples was poor. u-PA antigen concentration was increased and t-PA activity was decreased in aneurysmatic aortas. The results of the present study indicate that inflammatory reactions in human atherosclerotic vessels may be modulated by the fibrinolytic system, in particular by u-PA and PAI-2. Inflammatory activation and proteolytic activation may be interrelated via the u-PA-plasmin pathway. Atherosclerotic vessels are heterogeneous with respect to various important factors and results based on small vascular samples should be carefully evaluated. Furthermore, the value of small vascular samples in a clinical situation is likely to be low. Increased u-PA concentration in aortic aneurysms may promote proteolytic degradation of the vessel wall and decreased t-PA activity may contribute to mural thrombosis in the aneurysmal sac.