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

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; Kenn Holmbeck; Farideh Sabeh; Edward D Allen; Stephen J Weiss

doi:10.1084/jem.20050607

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

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

105 Citations (Scopus)

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.

Original language	English
Journal	The Journal of Experimental Medicine
Volume	202
Issue number	5
Pages (from-to)	663-71
Number of pages	9
ISSN	0022-1007
DOIs	https://doi.org/10.1084/jem.20050607
Publication status	Published - 5 Sept 2005

Keywords

Animals
Apoptosis/physiology
Arteries/metabolism
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
Matrix Metalloproteinases, Membrane-Associated
Mice
Mice, Mutant Strains
Microscopy, Electron
Myocytes, Smooth Muscle/metabolism
Reverse Transcriptase Polymerase Chain Reaction
Vascular Diseases/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1084/jem.20050607

Cite this

Filippov, S., Koenig, G. C., Chun, T.-H., Hotary, K. B., Ota, I., Bugge, T. H., Roberts, J. D., Fay, W. P., Birkedal-Hansen, H., Holmbeck, K., Sabeh, F., Allen, E. D., & Weiss, S. J. (2005). MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. The Journal of Experimental Medicine, 202(5), 663-71. https://doi.org/10.1084/jem.20050607

Filippov, S, Koenig, GC, Chun, T-H, Hotary, KB, Ota, I, Bugge, TH, Roberts, JD, Fay, WP, Birkedal-Hansen, H, Holmbeck, K, Sabeh, F, Allen, ED & Weiss, SJ 2005, 'MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells', The Journal of Experimental Medicine, vol. 202, no. 5, pp. 663-71. https://doi.org/10.1084/jem.20050607

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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.",

keywords = "Animals, Apoptosis/physiology, Arteries/metabolism, 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, Matrix Metalloproteinases, Membrane-Associated, Mice, Mice, Mutant Strains, Microscopy, Electron, Myocytes, Smooth Muscle/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Vascular Diseases/metabolism",

author = "Sergey Filippov and Koenig, {Gerald C} and Tae-Hwa Chun and Hotary, {Kevin B} and Ichiro Ota and Bugge, {Thomas H} and Roberts, {Joseph D} and Fay, {William P} and Henning Birkedal-Hansen and Kenn Holmbeck and Farideh Sabeh and Allen, {Edward D} and Weiss, {Stephen J}",

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doi = "10.1084/jem.20050607",

language = "English",

volume = "202",

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journal = "The Journal of Experimental Medicine",

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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 -

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

Abstract

Keywords

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