Matrix metalloproteinases generate angiostatin: Effects on neovascularization

Angiostatin, a cleavage product of plasminogen, has been shown to inhibit e ndothelial cell proliferation and metastatic tumor cell growth. Recently, t he production of angiostatin has been correlated with tumor-associated macr ophage production of elastolytic metalloproteinases in a murine model of Le wis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angio statin from plasminogen, Macrophage elastase (MMP-12 or MME) proved to be t he most efficient angiostatin-producing MMP, MME was followed by gelatinase s and then the stomelysins in catalytic efficiency; interstitial collagenas es had little capacity to generate angiostatin, Both recombinant angiostati n and angiostatin generated from recombinant MME-treated plasminogen inhibi ted human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice a nd their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microva scular endothelial cells.