Abstract
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.
| Original language | English |
|---|---|
| Journal | The Journal of Cell Biology |
| Volume | 167 |
| Issue number | 4 |
| Pages (from-to) | 757-67 |
| Number of pages | 11 |
| ISSN | 0021-9525 |
| DOIs | |
| Publication status | Published - 22 Nov 2004 |
Keywords
- Animals
- Blood Vessels/cytology
- Cell Membrane/metabolism
- Cells, Cultured
- Chick Embryo
- Collagen Type I/metabolism
- Endothelial Cells/cytology
- Extracellular Matrix/metabolism
- Gene Targeting
- Humans
- Hyaluronan Receptors/metabolism
- Integrin beta3/metabolism
- Male
- Matrix Metalloproteinase 14
- Matrix Metalloproteinase 2/metabolism
- Matrix Metalloproteinase 9/metabolism
- Matrix Metalloproteinases, Membrane-Associated
- Metalloendopeptidases/genetics
- Mice
- Mice, Knockout
- Models, Biological
- Neovascularization, Physiologic/physiology
- Phenotype
- Plasminogen/metabolism
- Receptors, Cell Surface/metabolism