PMID- 12154073
OWN - NLM
STAT- MEDLINE
DCOM- 20030416
LR  - 20220215
IS  - 0021-9533 (Print)
IS  - 0021-9533 (Linking)
VI  - 115
IP  - Pt 17
DP  - 2002 Sep 1
TI  - Endothelial tubulogenesis within fibrin gels specifically requires the activity 
      of membrane-type-matrix metalloproteinases (MT-MMPs).
PG  - 3427-38
AB  - Macro- and microvascular endothelial cells (EC) formed tubular structures when 
      cultured within a 3D fibrin matrix, a process that was enhanced by vascular 
      endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), hepatocyte 
      growth factor/scatter factor (HGF/SF) and an angiogenic cocktail composed of nine 
      angiogenic factors. Endothelial tubulogenesis was also increased in co-culture 
      with tumour cells such as U87 glioma cells, but not with non-tumorigenic cell 
      types such as Madin-Darby canine kidney (MDCK) epithelial cells. 
      VEGF/FGF-2-stimulated tube formation was dependent on metalloproteinase function 
      [it is inhibited by the addition of tissue inhibitor of metalloproteinases-2 
      (TIMP-2)], whereas aprotinin, E64 [trans-epoxysuccinyl-L-leucylamido 
      (4-guanidino)-butane] and pepstatin had no effect. In addition, TIMP-4 also 
      inhibited tubulogenesis, but TIMP-1 or the C-terminal haemopexin domain of matrix 
      metalloproteinase-2 (MMP-2) (PEX) and an anti-MMP-2 function-blocking antibody 
      were unable to block tube formation. This suggests that MMP-2 and other soluble 
      MMPs are not essential for tubulogenesis in fibrin gels, instead 
      TIMP-1-insensitive MMPs, such as members of the membrane type-MMPs (MT-MMP) 
      sub-group (MT1-, MT2-, MT3- or MT5-MMP), are required for this process. Further 
      support for a role for MT1-MMP in endothelial tubulogenesis is that recombinant 
      Y36G N-terminal TIMP-2 mutant protein, which retains an essentially unaltered 
      apparent inhibition constant (K(i)(app)) for several MMPs compared to wild-type 
      N-TIMP-2 but is a 40-fold poorer inhibitor of MT1-MMP, was unable to block 
      tubulogenesis. Furthermore, when EC were cultured within fibrin gels, the mRNA 
      levels of several MMPs (including MT1-MMP, MT2-MMP, MT3-MMP and MMP-2) increased 
      during tubulogenesis. Therefore MT-MMPs and specifically MT1-MMP are likely 
      candidates for involvement during endothelial tubulogenesis within a fibrin 
      matrix, and thus their blockade may be a viable strategy for inhibition of 
      angiogenesis.
FAU - Lafleur, Marc A
AU  - Lafleur MA
AD  - School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.
FAU - Handsley, Madeleine M
AU  - Handsley MM
FAU - Knauper, Vera
AU  - Knauper V
FAU - Murphy, Gillian
AU  - Murphy G
FAU - Edwards, Dylan R
AU  - Edwards DR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (Gels)
RN  - 0 (Growth Substances)
RN  - 0 (MMP15 protein, human)
RN  - 0 (MMP16 protein, human)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - 9001-31-4 (Fibrin)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 15)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 16)
RN  - EC 3.4.24.- (Matrix Metalloproteinases, Membrane-Associated)
RN  - EC 3.4.24.- (Metalloendopeptidases)
SB  - IM
MH  - Animals
MH  - Cell Culture Techniques/methods
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Endothelium, Vascular/cytology/drug effects/*growth & development
MH  - Fibrin/*metabolism
MH  - Gels
MH  - Growth Substances/pharmacology
MH  - Humans
MH  - Matrix Metalloproteinase 15
MH  - Matrix Metalloproteinase 16
MH  - Matrix Metalloproteinases, Membrane-Associated
MH  - Metalloendopeptidases/antagonists & inhibitors/*metabolism
MH  - Neovascularization, Physiologic/*physiology
MH  - Protease Inhibitors/metabolism
MH  - Time Factors
MH  - Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-2/genetics/metabolism
EDAT- 2002/08/03 10:00
MHDA- 2003/04/17 05:00
CRDT- 2002/08/03 10:00
PHST- 2002/08/03 10:00 [pubmed]
PHST- 2003/04/17 05:00 [medline]
PHST- 2002/08/03 10:00 [entrez]
AID - 10.1242/jcs.115.17.3427 [doi]
PST - ppublish
SO  - J Cell Sci. 2002 Sep 1;115(Pt 17):3427-38. doi: 10.1242/jcs.115.17.3427.