Three major groups of proteases play an important role in the processes that regulate angiogenesis, including the remodeling of the extracellular matrix, cell migration, and invasion, and the liberation and modification of growth factors. They comprise the Metalloproteinases, in particular the matrix metalloproteinases (MMPs), the cathepsin cysteine proteases and the serine proteases. The activities of these proteases are controlled by specific activation mechanisms and specific inhibitors, of which tissue inhibitors of metallo-proteinases (TIMPs), cystatins, and inhibitors of serine pro-teases called serpins represent major classes. Many of these proteases act on the cell surface either because they contain a membrane spanning or binding domain or as the result of their interaction with specific receptors on the cell surface. In addition, inhibitor studies with fumagillin derivatives have pointed to a role of aminopeptidases in angiogenesis.
The function of proteases in the angiogenic process is not limited to proteolysis of the basement membrane and extracellular matrix, which enables growth of the endothelial sprout Proteases also have indirect effects, as they activate other proteases and pro-angiogenic molecules. Proteases can also release angiogenic growth factors that may be sequestered in the extracellular matrix. In addition, proteolytic cleavage can generate molecules that inhibit angiogenesis. Among the serine proteases, the plasmin/ plasminogen activator system, in particular, is thought to play a major role.