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MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells.

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.
AuthorsSergey 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
JournalThe Journal of experimental medicine (J Exp Med) Vol. 202 Issue 5 Pg. 663-71 (Sep 05 2005) ISSN: 0022-1007 [Print] United States
PMID16147977 (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)

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