Vascular cell-derived fibrinolytic regulators and atherothrombotic vascular disorders (Review).
Fibrinolysis is essential for maintaining the fluency of blood flow. Attenuated fibrinolytic activity has been frequently detected in coronary artery disease, peripheral vascular diseases, diabetes, hyperlipidaemia and obesity. The biologically active product of fibrinolytic system is plasmin. Generation of plasmin is regulated by plasminogen activators (PA) and their inhibitors (PAI). Vascular endothelial and smooth muscle cells synthesize tissue-type and urokinase-type PA (tPA and uPA) and their major physiological inhibitor, PAI-1. The production of fibrinolytic regulators is modulated by a number of biological factors related to thrombosis and atherosclerosis, including coagulation factors, hormones, growth factors, inflammatory mediators and lipoproteins. Several anticoagulants, including heparin, hirudin and hirulog-1, affect the production of fibrinolytic regulators in vascular cells. Studies in knockout mice demonstrated that mice deficient in PA or plasminogen are susceptible to thrombosis during inflammation or injury. Overexpression of uPA or deficiency of PAI-1 promotes neointima and aneurysm formation, which is probably due to active remodelling of extracellular matrix in vascular wall caused by excess plasmin. Long-term effect of treatment with thrombolytic agents or in atheroscleronic cardiovascular diseases remains to be defined. Future studies on determination of the role of PA and PAI in vascular remodelling may help understand the mechanism for neointima formation and orient the prevention of restenosis following vascular procedures.
Shen
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Departments of Internal Medicine and Physiology, The University of Manitoba, Winnipeg, Manitoba, Canada.
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator