PLASMINOGEN ACTIVATORS AND MATRIX METALLOPROTEINASES IN ANGIOGENESIS

In the initial stages of capillary formation (angiogenesis) microvascu lar endothelial cells of preexisting blood vessels locally degrade the underlying basal lamina and invade into the stroma of the tissue to b e vascularized. A consistent body of experimental evidence has shown t hat this process requires a wide array of dedradative enzymes. Compone nts of the plasminogen activator (PA)-plasmin system and of the matrix metalloproteinase (MMP) family play important roles. PAs trigger a pr oteinase cascade that results is the generation of high local concentr ations of plasmin and active MMPs. This increase in proteolytic activi ty has three major consequences: it permits endothelial cell degradati on and invasion of the vessel basal lamina, generates extracellular ma trix (ECM) degradation products that are chemotactic for endothelial c ells, and activates and mobilizes growth factors localized in the ECM. In addition, urokinase-type PA modulates some endothelial cell functi ons, including proliferation and migration, with a mechanism independe nt of proteolytic activity. PA and MMP activities are modulated in end othelial cells by complex mechanisms, including transcriptional regula tion by a variety of growth factors and cytokines with angiogenic acti vity, extracellular control of the proteolytic activities by tissue in hibitors, and interaction with binding sites on the cell membrane and ECM.