MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix.
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., beta3 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.
Chun
Tae-Hwa
TH
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Sabeh
Farideh
F
Ota
Ichiro
I
Murphy
Hedwig
H
McDonagh
Kevin T
KT
Holmbeck
Kenn
K
Birkedal-Hansen
Henning
H
Allen
Edward D
ED
Weiss
Stephen J
SJ
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D024042:Collagen Type I / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D008297:Male; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010641:Phenotype; D010958:Plasminogen / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism
D024042:Collagen Type I; D018960:Hyaluronan Receptors; D039661:Integrin beta3; C507096:Mmp14 protein, mouse; D011956:Receptors, Cell Surface; D010958:Plasminogen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14