Abstract |
During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.
|
Authors | Sergey Filippov, Gerald C Koenig, Tae-Hwa Chun, Kevin B Hotary, Ichiro Ota, Thomas H Bugge, Joseph D Roberts, William P Fay, Henning Birkedal-Hansen, Kenn Holmbeck, Farideh Sabeh, Edward D Allen, Stephen J Weiss |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 202
Issue 5
Pg. 663-71
(Sep 05 2005)
ISSN: 0022-1007 [Print] United States |
PMID | 16147977
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
|
Chemical References |
- Mmp14 protein, mouse
- Collagen
- Matrix Metalloproteinases
- Matrix Metalloproteinases, Membrane-Associated
- Matrix Metalloproteinase 14
|
Topics |
- Animals
- Apoptosis
(physiology)
- Arteries
(metabolism, ultrastructure)
- Cell Movement
(physiology)
- Cloning, Molecular
- Collagen
(metabolism)
- Extracellular Matrix
(metabolism)
- Fluorescent Antibody Technique
- Gene Transfer Techniques
- In Situ Nick-End Labeling
- Male
- Matrix Metalloproteinase 14
- Matrix Metalloproteinases
(genetics, metabolism)
- Matrix Metalloproteinases, Membrane-Associated
- Mice
- Mice, Mutant Strains
- Microscopy, Electron
- Myocytes, Smooth Muscle
(metabolism, ultrastructure)
- Reverse Transcriptase Polymerase Chain Reaction
- Vascular Diseases
(metabolism)
|