Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling

Plasminogen activator inhibitor-I (PAI-I) is the principal inhibitor of urokinase type plasminogen activator (UPA) and tissue-type plasminopen activator (tPA), and as such is thought to play an important role in the regulation of' extracellular matrix remodeling. Ill blood, PAI-I is bound to the adhesion protein vitronectin and is associated with vitronectin in fibrin clots and the provisional matrix. Elevated levels of PAI-I are associated with atherosclerosis and an increased thrombotic tendency, while PAI-I deficiency leads to increased fibrinolysis and bleeding. PAI-I is also elevated in many solid tumors and is associated with a poor prognosis in cancer. PAI-I has been shown to be a potent regulator of both vascular cell rniLration in vitro and of angiogenesis and tumor growth in vivo. PAI-I can both promote and inhibit tumor growth and angiogenesis. Low concentrations of PAI-I can stimulate tumor angiogenesis while treatment of animals with high doses of PAI-I inhibits angiogenesis and tumor growth. Hence, PAI-I appears to have a multifunctional role in regulating the migratory and fibrinolytic activity of vascular cells, and this, in turn, may help to explain the many varied actions of PAI-I.