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Neointima formed by arterial smooth muscle cells expressing versican variant V3 is resistant to lipid and macrophage accumulation.

ABSTRACT: Extracellular matrix (ECM) of neointima formed following angioplasty contains elevated levels of versican, loosely arranged collagen, and fragmented deposits of elastin, features associated with lipid and macrophage accumulation. ECM with a low versican content, compact structure, and increased elastic fiber content can be achieved by expression of versican variant V3, which lacks chondroitin sulfate glycosaminoglycans. We hypothesized that V3-expressing arterial smooth muscle cells (ASMC) can be used to form a neointima resistant to lipid and macrophage accumulation associated with hypercholesterolemia.ASMC transduced with V3 cDNA were seeded into ballooned rabbit carotid arteries, and animals were fed a chow diet for 4 weeks, followed by a cholesterol-enriched diet for 4 weeks, achieving plasma cholesterol levels of 20 to 25 mmol/L. V3 neointimae at 8 weeks were compact, multilayered, and elastin enriched. They were significantly thinner (57%) than control neointimae; contained significantly more elastin (118%), less collagen (22%), and less lipid (76%); and showed significantly reduced macrophage infiltration (85%). Mechanistic studies demonstrated that oxidized low-density lipoprotein stimulated the formation of a monocyte-binding ECM, which was inhibited in the presence of V3 expressing ASMC.These results demonstrate that expression of V3 in vessel wall creates an elastin-rich neointimal matrix that in the presence of hyperlipidemia is resistant to lipid deposition and macrophage accumulation.

SUBMITTER: Merrilees MJ

PROVIDER: S-EPMC3123728 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Neointima formed by arterial smooth muscle cells expressing versican variant V3 is resistant to lipid and macrophage accumulation.

Merrilees Mervyn J MJ Beaumont Brent W BW Braun Kathleen R KR Thomas Anita C AC Kang Inkyung I Hinek Aleksander A Passi Alberto A Wight Thomas N TN

Arteriosclerosis, thrombosis, and vascular biology 20110324 6

<h4>Objective</h4>Extracellular matrix (ECM) of neointima formed following angioplasty contains elevated levels of versican, loosely arranged collagen, and fragmented deposits of elastin, features associated with lipid and macrophage accumulation. ECM with a low versican content, compact structure, and increased elastic fiber content can be achieved by expression of versican variant V3, which lacks chondroitin sulfate glycosaminoglycans. We hypothesized that V3-expressing arterial smooth muscle ...[more]

PMID: 21441139

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Project description:Arterial smooth muscle cells (ASMCs) undergo phenotypic changes during development and pathological processes in vivo and during cell culture in vitro. Our previous studies demonstrated that retrovirally-mediated expression of the versican V3 splice variant (V3) that lacks glycosaminoglycan chains by ASMCs retards cell proliferation and migration in vitro and reduces neointimal thickening, macrophage and lipid accumulation in animal models of vascular injury and atherosclerosis. However, the molecular pathways induced by V3 expression that are responsible for these changes are not yet clear. In the present study, we employed a microarray approach to examine how expression of V3 induced changes in gene expression and the molecular pathways in ASMCs. We found that forced expression of V3 by ASMCs affected expression of 521 genes by more than 1.5 fold. Gene ontology (GO) analysis shows that components of extracellular matrix were the most significantly affected by V3 expression, indicating that V3 expression elicits profound remodeling of extracellular matrix. In addition, genes regulating the formation of the cytoskeleton which also serve as markers of contractile smooth muscle cells were significantly upregulated. On the other hand, components of the complement system, chemokines, chemokine receptors, and transcription factors crucial for regulating inflammatory processes were among the genes most downregulated. Consistently, we found that the level of myocardin, a key transcription factor promoting contractile ASMC phenotype, was greatly increased while proinflammatory transcription factors NFkappaB1 and C/EBPβ were significantly attenuated in V3-expressing SMCs. Such results indicate that V3 expression reprograms ASMC into differentiated and anti-inflammatory phenotypes. Overall, these findings demonstrate that expression of V3 reprograms ASMCs promoting anti-inflammatory and differentiated smooth muscle cell phenotypes potentially by altering cell-ECM interaction and focal adhesion signaling pathways. Fischer rat ASMCs were transduced with either a retroviral vector expressing the Versican V3 splice variant (LV3SN) or an empty control vector (LXSN) in three independent experiments. In the first experiment, V3 and control transductions were performed with four technical replicates. In the subsequent two experiments, individual transductions were done for the V3 or control treatments. For data analysis, the technical replicates from the first experiment were averaged, and then data from the three experiments was evaluated in a paired manner.

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Neointima formed by arterial smooth muscle cells expressing versican variant V3 is resistant to lipid and macrophage accumulation.

Publications

Neointima formed by arterial smooth muscle cells expressing versican variant V3 is resistant to lipid and macrophage accumulation.

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