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Published online 15 November 2004. doi:10.1083/jcb.200405001
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 757-767
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Article

MT1-MMP–dependent neovessel formation within the confines of the three-dimensional extracellular matrix



Tae-Hwa Chun1, Farideh Sabeh1, Ichiro Ota1, Hedwig Murphy3, Kevin T. McDonagh2, Kenn Holmbeck4, Henning Birkedal-Hansen4, Edward D. Allen1, and Stephen J. Weiss1

1 Division of Molecular Medicine and Genetics, Department of Internal Medicine
2 Division of Hematology/Oncology, Department of Internal Medicine
3 Department of Pathology, University of Michigan, Ann Arbor, MI 48109
4 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892

Correspondence to Stephen J. Weiss: sjweiss{at}umich.edu

During angiogenesis, endothelial cells initiate a tissue-invasive program within an interstitial matrix comprised largely of type I collagen. Extracellular matrix–degradative enzymes, including the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, are thought to play key roles in angiogenesis by binding to docking sites on the cell surface after activation by plasmin- and/or membrane-type (MT) 1-MMP–dependent processes. To identify proteinases critical to neovessel formation, an ex vivo model of angiogenesis has been established wherein tissue explants from gene-targeted mice are embedded within a three-dimensional, type I collagen matrix. Unexpectedly, neither MMP-2, MMP-9, their cognate cell-surface receptors (i.e., ß3 integrin and CD44), nor plasminogen are essential for collagenolytic activity, endothelial cell invasion, or neovessel formation. Instead, the membrane-anchored MMP, MT1-MMP, confers endothelial cells with the ability to express invasive and tubulogenic activity in a collagen-rich milieu, in vitro or in vivo, where it plays an indispensable role in driving neovessel formation.

Abbreviations used in this paper: 3-D, three-dimensional; CAM, chorioallantoic membrane; HGF, hepatocyte growth factor; MMP, matrix metalloproteinase; MT, membrane-type; TIMP, tissue inhibitor of metalloproteinase.


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