Membrane-Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions

J Am Heart Assoc. 2017 Jul 22;6(7):e003693. doi: 10.1161/JAHA.116.003693.

Abstract

Background: The MMP (matrix metalloproteinase) family plays diverse and critical roles in directing vascular wall remodeling in atherosclerosis. Unlike secreted-type MMPs, a member of the membrane-type MMP family, MT1-MMP (membrane-type 1 MMP; MMP14), mediates pericellular extracellular matrix degradation that is indispensable for maintaining physiological extracellular matrix homeostasis. However, given the premature mortality exhibited by MT1-MMP-null mice, the potential role of the proteinase in atherogenesis remains elusive. We sought to determine the effects of both MT1-MMP heterozygosity and tissue-specific gene targeting on atherogenesis in APOE (apolipoprotein E)-null mice.

Methods and results: MT1-MMP heterozygosity in the APOE-null background (Mmp14+/-Apoe-/- ) significantly promoted atherogenesis relative to Mmp14+/+Apoe-/- mice. Furthermore, the tissue-specific deletion of MT1-MMP from vascular smooth muscle cells (VSMCs) in SM22α-Cre(+)Mmp14F/FApoe-/- (VSMC-knockout) mice likewise increased the severity of atherosclerotic lesions. Although VSMC-knockout mice also developed progressive atherosclerotic aneurysms in their iliac arteries, macrophage- and adipose-specific MT1-MMP-knockout mice did not display this sensitized phenotype. In VSMC-knockout mice, atherosclerotic lesions were populated by hyperproliferating VSMCs (smooth muscle actin- and Ki67-double-positive cells) that were characterized by a proinflammatory gene expression profile. Finally, MT1-MMP-null VSMCs cultured in a 3-dimensional spheroid model system designed to mimic in vivo-like cell-cell and cell-extracellular matrix interactions, likewise displayed markedly increased proliferative potential.

Conclusions: MT1-MMP expressed by VSMCs plays a key role in limiting the progression of atherosclerosis in APOE-null mice by regulating proliferative responses and inhibiting the deterioration of VSMC function in atherogenic vascular walls.

Keywords: aneurysm; atherosclerosis; inflammation; matrix metalloproteinases; muscle; smooth.

MeSH terms

  • Animals
  • Aorta / enzymology
  • Aorta / pathology
  • Aortic Diseases / enzymology*
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Cell Communication
  • Cell Proliferation*
  • Cell-Matrix Junctions / enzymology
  • Cell-Matrix Junctions / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Iliac Artery / enzymology
  • Iliac Artery / pathology
  • Inflammation Mediators / metabolism
  • Male
  • Matrix Metalloproteinase 14 / deficiency
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Phenotype
  • Plaque, Atherosclerotic
  • Signal Transduction
  • Vascular Remodeling

Substances

  • Inflammation Mediators
  • Mmp14 protein, mouse
  • Matrix Metalloproteinase 14