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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(+)Mmp14 F/F Apoe -/- (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.

journal_name

J Am Heart Assoc

journal_title

Journal of the American Heart Association

authors

Barnes RH 2nd,Akama T,Öhman MK,Woo MS,Bahr J,Weiss SJ,Eitzman DT,Chun TH

doi

10.1161/JAHA.116.003693

subject

Has Abstract

pub_date

2017-07-22 00:00:00

issue

issn

2047-9980

pii

JAHA.116.003693

journal_volume

pub_type

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