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

Mervyn Merrilees, Brett Beaumont, Kathleen Braun, Anita C Thomas, Inkyung Kang, Aleksander Hinek, Alberto Passi, Thomas Wight

Research output: Contribution to journalArticle (Academic Journal)peer-review

33 Citations (Scopus)

Abstract

OBJECTIVE: 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. METHODS AND RESULTS: 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 this monocyte-binding ECM, which was inhibited in the presence of V3 expressing ASMC. CONCLUSIONS: 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
Original languageEnglish
Pages (from-to)1309-1316
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Publication statusPublished - 2011

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