title: 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.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Filippov
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Koenig
authors.forename: Tae-Hwa
authors.initials: TH
authors.lastname: Chun
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Hotary
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ota
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Roberts
authors.forename: William P
authors.initials: WP
authors.lastname: Fay
authors.forename: Henning
authors.initials: H
authors.lastname: Birkedal-Hansen
authors.forename: Kenn
authors.initials: K
authors.lastname: Holmbeck
authors.forename: Farideh
authors.initials: F
authors.lastname: Sabeh
authors.forename: Edward D
authors.initials: ED
authors.lastname: Allen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001158:Arteries / Q000378:metabolism* / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology*; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D053511:Matrix Metalloproteinase 14; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014652:Vascular Diseases / Q000378:metabolism*
chemical_list: C507096:Mmp14 protein, mouse; D003094:Collagen; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D053511:Matrix Metalloproteinase 14