Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs)

Lafleur, Marc A., Handsley, Madeleine M., Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Murphy, Gillian and Edwards, Dylan R. 2002. Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). Journal of Cell Science 115 (17) , pp. 3427-3438.

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	Q Science > Q Science (General)
Uncontrolled Keywords:	MT-MMPs; Fibrin gels; Tubulogenesis; Endothelial; Angiogenesis.
Publisher:	The Company of Biologists Ltd
ISSN:	0021-9533
Last Modified:	27 Oct 2022 10:13
URI:	https://orca.cardiff.ac.uk/id/eprint/69338

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