Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins.
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.
Hiraoka
N
N
Department of Internal Medicine and University of Michigan Comprehensive Cancer Center, Ann Arbor 48109, USA.
Allen
E
E
Apel
I J
IJ
Gyetko
M R
MR
Weiss
S J
SJ
D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D005347:Fibroblasts; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000494:pharmacology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D009130:Muscle, Smooth; D018919:Neovascularization, Physiologic; D010958:Plasminogen / Q000172:deficiency / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism; D051381:Rats; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; C507096:Mmp14 protein, mouse; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017228:Hepatocyte Growth Factor; D005337:Fibrin; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D053511:Matrix Metalloproteinase 14