Forskning ved Københavns Universitet - Københavns Universitet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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
  • Holmbeck, Kenn
  • Farideh Sabeh
  • Edward D Allen
  • Stephen J Weiss

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.

OriginalsprogEngelsk
TidsskriftThe Journal of Experimental Medicine
Vol/bind202
Udgave nummer5
Sider (fra-til)663-71
Antal sider9
ISSN0022-1007
DOI
StatusUdgivet - 5 sep. 2005

ID: 201165364