KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis

Abstract

Herein we employ Myh11-CreERT2 ROSA floxed STOP eYFP Apoe−/− smooth muscle cell (SMC) lineage tracing mice to show that traditional methods for detecting SMCs based on immuno-staining fail to detect > 80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages including macrophages (Mϕs), and mesenchymal stem cells (MSCs). SMC-specific conditional knockout (KO) of Krüppel-like factor 4 (KLF4) resulted in reduced numbers of SMC-derived MSC-, and Mϕ-like cells, marked reductions in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness. Results of in vivo KLF4 ChIP-Seq analyses, and studies in cultured SMC treated with cholesterol identified > 800 KLF4 target genes including many that regulate pro-inflammatory responses of SMC. Results indicate that the contribution of SMCs within atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.

Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation

“…[46][47][48] Along these lines, recent studies have shown transdifferentiation of SMCs into a lipid-loaded, foam cell-like state during atherosclerosis. [49][50][51] These studies suggest that SMCs may not only contribute to fibrous cap formation and calcification but also directly participate in the process of atheroma formation through macrophage foam cell formation, accounting for $18-40% Mac2/CD68-positive cells observed in human and mouse atherosclerotic lesions. 49 to control myeloid differentiation necessary for monocyte/macrophage and osteoclast formation, [46][47][48] their transcriptional activities may also be critical in controlling the SMC to macrophage/foam cell-like differentiation.…”

“…[49][50][51] These studies suggest that SMCs may not only contribute to fibrous cap formation and calcification but also directly participate in the process of atheroma formation through macrophage foam cell formation, accounting for $18-40% Mac2/CD68-positive cells observed in human and mouse atherosclerotic lesions. 49 to control myeloid differentiation necessary for monocyte/macrophage and osteoclast formation, [46][47][48] their transcriptional activities may also be critical in controlling the SMC to macrophage/foam cell-like differentiation. Therefore, the dominant negative effect of truncated Runx2 in both bone marrow-derived cells and SMCs could act synergistically to prevent atheromatous plaque formation as seen in the Sun et al 21 study, though a detailed mechanism would require further investigation.…”

Erratum: Inflammatory processes in cardiovascular disease: a route to targeted therapies

“…A number of experiments in mice, and notably humans [131][132][133] , have produced in vivo data consistent with these phenomena: 30-40% of cells classified as plaque macrophages were of vascular smooth muscle cell origin. It is too early to discern the contribution of these cells to the pathological process during atherogenesis, but at least in cell culture, they do not share the molecular signature or the functional properties of activated macrophages 134 .…”

“…Depending on their local environment, T lymphocytes can be stimulated to secrete proinflammatory T h 1 cytokines such IL-1, IL-6, and TNF; or T h 2 cytokines such as IL-4, IL-10, and IL-13, which promote resolution of inflammation. IL-1 and TNF signalling is primarily mediated by p38 mitogen- [131][132][133] , have produced in vivo data consistent with these phenomena: 30-40% of cells classified as plaque macrophages were of vascular smooth muscle cell origin. It is too early to discern the contribution of these cells to the pathological process during atherogenesis, but at least in cell culture, they do not share the molecular signature or the functional properties of activated macrophages 134 .…”

Radiosensitive Smooth Muscle Cells Populate Neointimal Lesions Through a Platelet Derived Growth Factor Receptor Beta Dependent Mechanism

“…Interestingly, recent studies by our lab 6,7 and others 8,9 have begun to demonstrate that SMCs are capable of many more functions than those just related to contraction, dilation, and ECM deposition. The role of SMCs in alternative pathways is thought to be mediated through a process known as SMC phenotypic switching.…”