Abstract
During angiogenesis, endothelial cells penetrate fibrin barriers via undefined proteolytic mechanisms. We demonstrate that the fibrinolytic plasminogen activator (PA)-plasminogen system is not required for this process, since tissues isolated from PA- or plasminogen-deficient mice successfully neovascularize fibrin gels. By contrast, neovessel formation, in vitro and in vivo, is dependent on fibrinolytic, endothelial cell-derived matrix metalloproteinases (MMP). MMPs directly regulate this process as invasion-incompetent cells penetrate fibrin barriers when transfected with the most potent fibrinolytic metalloproteinase identified in endothelium, membrane type-1 MMP (MT1-MMP). Membrane display of MT1-MMP is required, as invasion-incompetent cells expressing a fibrinolytically active, transmembrane-deleted form of MT1-MMP remain noninvasive. These observations identify a PA-independent fibrinolytic pathway wherein tethered MMPs function as pericellular fibrinolysins during the neovascularization process.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aorta / cytology
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Cells, Cultured
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Endothelial Growth Factors / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / enzymology
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Fibrin / drug effects
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Fibrin / metabolism*
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Fibrinolysin / metabolism
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Fibrinolysis
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Fibroblasts
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Hepatocyte Growth Factor / pharmacology
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Humans
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Lymphokines / pharmacology
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Matrix Metalloproteinase 14
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Matrix Metalloproteinase 3 / genetics
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Matrix Metalloproteinase 3 / pharmacology
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases / metabolism*
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Mice
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Muscle, Smooth
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Neovascularization, Physiologic*
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Plasminogen / deficiency
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Plasminogen / metabolism
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Plasminogen Activators / metabolism
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Rats
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Transforming Growth Factor alpha / pharmacology
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Lymphokines
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Mmp14 protein, mouse
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Transforming Growth Factor alpha
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Hepatocyte Growth Factor
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Fibrin
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Plasminogen
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Plasminogen Activators
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Fibrinolysin
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 14