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

TY - JOUR

T1 - MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix

AU - Chun, Tae-Hwa

AU - Sabeh, Farideh

AU - Ota, Ichiro

AU - Murphy, Hedwig

AU - McDonagh, Kevin T

AU - Holmbeck, Kenn

AU - Birkedal-Hansen, Henning

AU - Allen, Edward D

AU - Weiss, Stephen J

PY - 2004/11/22

Y1 - 2004/11/22

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Vessels/cytology

KW - Cell Membrane/metabolism

KW - Cells, Cultured

KW - Chick Embryo

KW - Collagen Type I/metabolism

KW - Endothelial Cells/cytology

KW - Extracellular Matrix/metabolism

KW - Gene Targeting

KW - Humans

KW - Hyaluronan Receptors/metabolism

KW - Integrin beta3/metabolism

KW - Male

KW - Matrix Metalloproteinase 14

KW - Matrix Metalloproteinase 2/metabolism

KW - Matrix Metalloproteinase 9/metabolism

KW - Matrix Metalloproteinases, Membrane-Associated

KW - Metalloendopeptidases/genetics

KW - Mice

KW - Mice, Knockout

KW - Models, Biological

KW - Neovascularization, Physiologic/physiology

KW - Phenotype

KW - Plasminogen/metabolism

KW - Receptors, Cell Surface/metabolism

U2 - 10.1083/jcb.200405001

DO - 10.1083/jcb.200405001

M3 - Journal article

C2 - 15545316

SN - 0021-9525

VL - 167

SP - 757

EP - 767

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 4

ER -