REGULATION AND ROLE OF UROKINASE PLASMINOGEN-ACTIVATOR IN VASCULAR REMODELING

1. Urokinase plasminogen activator (uPA) is produced and secreted by m ultiple vascular cell types, thus influencing the processes and the ex tent to which the vasculature is remodelled during the development of the intima or a neointima and during hypertrophy and angiogenesis. 2. Urokinase plasminogen activator mRNA expression is up- and down-regula ted by growth factors, cytokines and steroids. Urokinase plasminogen a ctivator is secreted as a single chain inactive form that may be prote olytically converted to active or inactive forms. Targeting of proteol ytic activity may occur via focalized expression of uPA and its cell s urface receptors (uPAR). Proteolytic activity is also controlled throu gh the often co-ordinated expression of specific inhibitors. 3. A prot eolytic cascade involving uPA provides its major role in tissue remode lling through the primary degradation of extracellular matrix and seco ndarily through the activation of transforming growth factor-beta or r elease from the matrix of basic fibroblast growth factor. In addition, uPA secreted by growth factor-stimulated vascular cells may contribut e to the chemotactic and mitogenic responses ascribed to the growth fa ctor and recent evidence strongly suggests that uPA has direct biologi cal actions on vascular cells. 4. The cell surface binding of uPA via its growth factor-like domain to uPAR localizes and activates the prot ease, but may also initiate transmembrane signalling of biological res ponses, including migration/invasion and proliferation. As the uPAR la cks intracellular signalling domains, the signals may be transduced vi a interactions between uPA/uPAR and more classical signalling receptor s. The mechanism by which uPA may be involved in cell signalling is ye t to be elucidated.