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

DOI PDF 被引用文献3件
  • Sergey Filippov
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Gerald C. Koenig
    2Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Tae-Hwa Chun
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Kevin B. Hotary
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Ichiro Ota
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Thomas H. Bugge
    3Protease and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
  • Joseph D. Roberts
    2Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • William P. Fay
    2Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Henning Birkedal-Hansen
    4Matrix Metalloproteinase Unit, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
  • Kenn Holmbeck
    4Matrix Metalloproteinase Unit, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
  • Farideh Sabeh
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Edward D. Allen
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
  • Stephen J. Weiss
    1Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

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<jats:p>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.</jats:p>

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