Vascular plasminogen activator

Levin RI, Harpel PC, Weil D, Chang TS, Rifkin DB. Aspirin inhibits vascular plasminogen activator activity in vivo. Studies utilizing a new assay to quantify plasminogen activator activity. J Clin Invest 1984 74 571-80. 

The concentration of t-PA in human blood is 2—5 ng/mL, ie, 2—5 ppb. Plasminogen activation is accelerated in the presence of a clot, but the rate is slow. The dissolution of a clot requites a week or more during normal repair of vascular damage (17). Prevention of irreversible tissue damage during a heart attack requires that a clot, formed by mpture of an atherosclerotic plaque, be dissolved in a matter of hours. This rapid thrombolysis (dissolution of the clot) must be achieved without significant tibrinogenolysis elsewhere in the patient. 

Tissue plasminogen activator (alteplase t-PA) is a serine protease that is released into the circulation from vascular endothelium under conditions of injury or... 

The role of the fibrinolytic system is to dissolve any clots that are formed within the intact vascular system and so restrict clot formation to the site of injury. The digestion of the fibrin and hence its lysis is catalysed by the proteolytic enzyme, plasmin, another serine proteinase. Plasmin is formed from the inactive precursor, plasminogen, by the activity of yet other proteolytic enzymes, urokinase, streptokinase and tissue plasminogen activator (tPA) which are also serine proteinases. These enzymes only hydrolyse plasminogen that is bound to the fibrin. Any plasmin that escapes into the general circulation is inactivated by binding to a serpin (Box 17.2). 

The fibrin thrombus resulting from blood clotting (see p. 290) is dissolved again by plasmin, a serine proteinase found in the blood plasma. For this purpose, the precursor plasminogen first has to be proteolyti-cally activated by enzymes from various tissues. This group includes the plasminogen activator from the kidney (urokinase) and tissue plasminogen activator (t-PA) from vascular endothelia. By contrast, the plasma protein a2-antiplasmin, which binds to active plasmin and thereby inactivates it, inhibits fibrinolysis. 

Olofsson, B., Korpelainen, E., Pepper, M.S., Mandriota, S.J., Aase, K., Kumar, V., Gunji, Y., Jeltsch, M.M., Shibuya, M., Alitalo, K. and Eriksson, U. (1998) Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc. Natl Acad. Sci. USA, 95, 11709-11714. 

Diagrammatic representation of actions of VEGF and receptors. Abbreviations HIF-1, hypoxia-inducible factor LPA, lysophosphatidic acid ox-LDL, oxidized low-density PAl, plasminogen activation inhibitor PIGF, placental growth factor VEGF, vascular endothelial growth factor. 

Tissue plasminogen activator (t-PA) is an endogenous serine protease synthesized and secreted by the vascular endothelium. It is present in all human tissues. With the exception of liver and spleen, tissue concentration correlates directly with vascularity. 

Caplan LR, Schlaug G (2002) Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke 33 2066-2071... 

Erickson LA, Fici GJ, Lund JE et al. (1990) Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 346 74—76 Kawasaki T, Dewerchin M, Lijnen HR et al. (2000) Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice. Blood 96 153-160... 

Pinsky DJ, Liao H, Lawson CA et al. (1998) Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 102 919-928... 

Eitzman DT, Westrick RJ, Nabel EG, Ginsburg D (2000) Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 95 577-580 Zheng X, Sunders TL, Camper S A et al. (1995) Vitronectin is not essential for normal mammalian development and fertility. Proc Natl Acad Sci USA 92 12426-12430... 

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