Title
Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix
Author
Collen, A.
Hanemaaijer, R.
Lupu, F.
Quax, P.H.A.
van Lent, N.
Grimbergen, J.
Peters, E.
Koolwijk, P.
van Hinsbergh, V.W.M.
Gaubius Instituut TNO
Publication year
2003
Abstract
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.
Subject
Biology
Biomedical Research
Adenoviridae
Aprotinin
Cells, Cultured
Collagen
Culture Media
Defective Viruses
Drug Synergism
Endothelial Growth Factors
Endothelium, Vascular
Fibrin
Fibroblast Growth Factor 2
Genetic Vectors
Heart Diseases
Humans
Intercellular Signaling Peptides and Proteins
Lymphokines
Matrix Metalloproteinase 1
Matrix Metalloproteinase 2
Matrix Metalloproteinases, Membrane-Associated
Metalloendopeptidases
Neovascularization, Pathologic
Neovascularization, Physiologic
Phenylalanine
Protease Inhibitors
Thiophenes
Thrombosis
Tissue Inhibitor of Metalloproteinase-1
Tissue Inhibitor of Metalloproteinase-3
Transduction, Genetic
Tumor Necrosis Factor-alpha
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
To reference this document use:
http://resolver.tudelft.nl/uuid:ed94deb5-b5c5-4d5f-bbb7-6e12381e4708
DOI
https://doi.org/10.1182/blood-2002-05-1593
TNO identifier
236997
ISSN
0006-4971
Source
Blood, 101 (5), 1810-1817
Document type
article