Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix
article
Adult angiogenesis, associated with pathologic conditions, is often accompanied by the formation of a fibrinous exudate. This temporary matrix consists mainly of fibrin but is intermingled with plasma proteins and collagen fibers. The formation of capillary structures in a fibrinous matrix in vivo was mimicked by an in vitro model, in which human microvascular endothelial cells (hMVECs) seeded on top of a fibrin-10% collagen matrix form capillarylike tubular structures after stimulation with basic fibroblast growth factor/tumor necrosis factor α (bFGF/TNF-α) or vascular endothelial growth factor (VEGF)/TNF-α. In the fibrin-collagen matrix the metalloproteinase inhibitor BB94 inhibited tubule formation by 70% to 80%. Simultaneous inhibition of plasmin and metalloproteinases by aprotinin and BB94 caused a nearly complete inhibition of tubule formation. Adenoviral transduction of tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-3 into endothelial cells revealed that TIMP-3 markedly inhibited angiogenesis, whereas TIMP-1 had only a minor effect. Immunohistochemical analysis showed the presence of matrix metalloproteinase 1 (MMP-1), MMP-2, and membrane-type 1 (MT1)-MMP, whereas MMP-9 was absent. The endothelial production of these MMPs was confirmed by antigen assays and real-time polymerase chain reaction (PCR). MT1-MMP mRNA was markedly increased in endothelial cells under conditions that induced tubular structures. The presence of MMP-1, MMP-2, and MT1-MMP was also demonstrated in vivo in the newly formed vessels of a recanalized arterial mural thrombus. These data suggest that MMPs, in particular MT-MMPs, play a pivotal role in the formation of capillarylike tubular structures in a collagen-containing fibrin matrix in vitro and may be involved in angiogenesis in a fibrinous exudate in vivo. © 2003 by The American Society of Hematology.
Topics
Biomedical ResearchAdenoviridaeAprotininCells, CulturedCollagenCulture MediaDefective VirusesDrug SynergismEndothelial Growth FactorsEndothelium, VascularFibrinFibroblast Growth Factor 2Genetic VectorsHeart DiseasesHumansIntercellular Signaling Peptides and ProteinsLymphokinesMatrix Metalloproteinase 1Matrix Metalloproteinase 2Matrix Metalloproteinases, Membrane-AssociatedMetalloendopeptidasesNeovascularization, PathologicNeovascularization, PhysiologicPhenylalanineProtease InhibitorsThiophenesThrombosisTissue Inhibitor of Metalloproteinase-1Tissue Inhibitor of Metalloproteinase-3Transduction, GeneticTumor Necrosis Factor-alphaVascular Endothelial Growth Factor AVascular Endothelial Growth Factors
TNO Identifier
236997
ISSN
00064971
Source
Blood, 101(5), pp. 1810-1817.
Pages
1810-1817
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