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,
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Divisions of
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Dermatology and
Respiratory and Critical Care, Departments of
Medicine,
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Pediatrics, and
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Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110; and
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Monsanto/Searle Co., St. Louis, MO 63141
Angiostatin, a cleavage product of plasminogen, has been shown to inhibit endothelial cell proliferation and metastatic tumor cell growth. Recently, the production of angiostatin has been correlated with tumor-associated macrophage production of elastolytic metalloproteinases in a murine model of Lewis lung cell carcinoma. In this report we demonstrate that purified murine and human matrix metalloproteinases generate biologically functional angiostatin from plasminogen. Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostatin-producing MMP. MME was followed by gelatinases and then the stomelysins in catalytic efficiency; interstitial collagenases had little capacity to generate angiostatin. Both recombinant angiostatin and angiostatin generated from recombinant MME-treated plasminogen inhibited human microvascular endothelial cell proliferation and differentiation in vitro. Finally, employing macrophages isolated from MME-deficient mice and their wild-type littermates, we demonstrate that MME is required for the generation of angiostatin that inhibits the proliferation of human microvascular endothelial cells.
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O. Hiller, A. Lichte, A. Oberpichler, A. Kocourek, and H. Tschesche Matrix Metalloproteinases Collagenase-2, Macrophage Elastase, Collagenase-3, and Membrane Type 1-Matrix Metalloproteinase Impair Clotting by Degradation of Fibrinogen and Factor XII J. Biol. Chem., October 13, 2000; 275(42): 33008 - 33013. [Abstract] [Full Text] [PDF]
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S. L. Raza, L. C. Nehring, S. D. Shapiro, and L. A. Cornelius Proteinase-activated Receptor-1 Regulation of Macrophage Elastase (MMP-12) Secretion by Serine Proteinases J. Biol. Chem., December 22, 2000; 275(52): 41243 - 41250. [Abstract] [Full Text] [PDF]
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 A. Pozzi, P. E. Moberg, L. A. Miles, S. Wagner, P. Soloway, and H. A. Gardner Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization PNAS, February 29, 2000; 97(5): 2202 - 2207. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, J. Gannon, M. Aikawa, F. J. Schoen, E. Rabkin, L. Lopresti-Morrow, J. Crawford, S. Black, P. Libby, P. G. Mitchell, et al. Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction Circulation, February 12, 2002; 105(6): 753 - 758. [Abstract] [Full Text] [PDF]
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