Granulocyte‐macrophage colony stimulating factor induces endothelial capillary formation through induction of membrane‐type 1 matrix metalloproteinase expression in vitro

Krubasik, Davia, Eisenach, Patricia A., Kunz-Schughart, Leoni A., Murphy, Gillian and English, William R. ORCID: https://orcid.org/0000-0003-3024-2441 (2008) Granulocyte‐macrophage colony stimulating factor induces endothelial capillary formation through induction of membrane‐type 1 matrix metalloproteinase expression in vitro. International Journal of Cancer, 122 (6). pp. 1261-1272. ISSN 1097-0215

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Abstract

In our study, we examined the mechanism by which granulocyte-macrophage colony stimulating factor (GM-CSF) regulates angiogenesis using in vitro models. GM-CSF significantly increased precapillary sprout-like formation from endothelial cell spheroids seeded in type-I collagen gels and tubule formation on coculture of endothelial cells with fibroblasts. In both cases, sprout and tubule formation was highly dependent on metalloproteinase activity. Tissue Inhibitor of metalloproteinase (TIMP) profiling in the spheroid and coculture models showed inhibition by TIMP-2 but not by TIMP-1, indicative of activity of membrane-type matrix metalloproteinases (MT-MMPs). GM-CSF induced sprout formation in spheroids was found to be potently inhibited by siRNA specific for MT1-MMP. Subsequent analysis showed that GM-CSF transiently increased MT1-MMP mRNA in endothelial cells in a MEK-dependent mechanism, which led to increased surface levels of MT1-MMP. This was accompanied by an increase in MT1-MMP-dependent degradation of DQ-collagen by lysates of GM-CSF stimulated endothelial cells. GM-CSF did not increase MT1-MMP levels in fibroblasts. The effect of GM-CSF on endothelial cell sprout formation could be mimicked by adenoviral transduction of intact spheroids with virus expressing MT1-MMP, but not by transduction of endothelial cells before spheroid formation, suggesting that upregulation of MT1-MMP must only occur in cells directly involved in tubule formation. © 2007 Wiley-Liss, Inc.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	15 Dec 2022 10:31
Last Modified:	19 Oct 2023 03:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/90195
DOI:	10.1002/ijc.23234

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