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

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.

• Authors: Richard H Barnes 2nd, Takeshi Akama, Miina K Öhman, Moon-Sook Woo, Julian Bahr, Stephen J Weiss, Daniel T Eitzman, Tae-Hwa Chun
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 6 Issue 7 (Jul 22 2017) ISSN: 2047-9980 [Electronic] England
• PMID: 28735290 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Chemical References

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

Topics

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