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

Abstract

BackgroundThe 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 ResultsMT1‐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. ConclusionsMT1‐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