Matrix metalloproteinases generate angiostatin: effects on neovascularization.
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.
Cornelius
L A
LA
Division of Dermatology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA. lcorneli@imgate.wustl.edu
Nehring
L C
LC
Harding
E
E
Bolanowski
M
M
Welgus
H G
HG
Kobayashi
D K
DK
Pierce
R A
RA
Shapiro
S D
SD
D000577:Amides / Q000494:pharmacology; D043168:Angiostatins; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D018093:Gelatinases / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D017737:Macrophages, Peritoneal / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D019278:Matrix Metalloproteinase 3 / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D010958:Plasminogen / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000577:Amides; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; C065557:N-(2-isobutyl-3-(N'-hydroxycarbonylamido)propanoyl)-O-methyltyrosinemethylamide; D014443:Tyrosine; D043168:Angiostatins; D010958:Plasminogen; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12