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

TY - JOUR

T1 - MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells

AU - Filippov, Sergey

AU - Koenig, Gerald C

AU - Chun, Tae-Hwa

AU - Hotary, Kevin B

AU - Ota, Ichiro

AU - Bugge, Thomas H

AU - Roberts, Joseph D

AU - Fay, William P

AU - Birkedal-Hansen, Henning

AU - Holmbeck, Kenn

AU - Sabeh, Farideh

AU - Allen, Edward D

AU - Weiss, Stephen J

PY - 2005/9/5

Y1 - 2005/9/5

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis/physiology

KW - Arteries/metabolism

KW - Cell Movement/physiology

KW - Cloning, Molecular

KW - Collagen/metabolism

KW - Extracellular Matrix/metabolism

KW - Fluorescent Antibody Technique

KW - Gene Transfer Techniques

KW - In Situ Nick-End Labeling

KW - Male

KW - Matrix Metalloproteinase 14

KW - Matrix Metalloproteinases/genetics

KW - Matrix Metalloproteinases, Membrane-Associated

KW - Mice

KW - Mice, Mutant Strains

KW - Microscopy, Electron

KW - Myocytes, Smooth Muscle/metabolism

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Vascular Diseases/metabolism

U2 - 10.1084/jem.20050607

DO - 10.1084/jem.20050607

M3 - Journal article

C2 - 16147977

SN - 0022-1007

VL - 202

SP - 663

EP - 671

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

IS - 5

ER -