Role of Smooth Muscle Cells in the Initiation and Early Progression of Atherosclerosis

Abstract

Abstract-The initiation of atherosclerosis results from complex interactions of circulating factors and various cell types in the vessel wall, including endothelial cells, lymphocytes, monocytes, and smooth muscle cells (SMCs). Recent reviews highlight the role of activated endothelium and inflammatory cell recruitment in the initiation of and progression of early atherosclerosis. Yet, human autopsy studies, in vitro mechanistic studies, and in vivo correlative data suggest an important role for SMCs in the initiation of atherosclerosis. SMCs are the major producers of extracellular matrix within the vessel wall and in response to atherogenic stimuli can modify the type of matrix proteins produced. In turn, the type of matrix present can affect the lipid content of the developing plaque and the proliferative index of the cells that are adherent to it. SMCs are also capable of functions typically attributed to other cell types. Like macrophages, SMCs can express a variety of receptors for lipid uptake and can form foam-like cells, thereby participating in the early accumulation of plaque lipid. Like endothelial cells, SMCs can also express a variety of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 to which monocytes and lymphocytes can adhere and migrate into the vessel wall. In addition, through these adhesion molecules, SMCs can also stabilize these cells against apoptosis, thus contributing to the early cellularity of the lesion. Like many cells within the developing plaque, SMCs also produce many cytokines such as PDGF, transforming growth factor-␤, IFN␥, and MCP-1, all of which contribute to the initiation and propagation of the inflammatory response to lipid. Recent advances in SMC-specific gene modulation have enhanced our ability to determine the role of SMCs in early atherogenesis.

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

“…17,38,39 In human atheroma, endothelial cells and smooth muscle cells also elaborate cytokines and contribute to the overall inflammatory state. 40,41 Therefore, it was logical to test whether or not reduced Rap1 levels can diminish the release of NFkB-mediated pro-inflammatory mediators in endothelial and vascular smooth muscle cells. Modulation of Rap1 levels had no effect on IL-8, IL-1b, ICAM-1, VCAM-1, E-selectin and Pselectin expression in activated endothelial cells and did not affect IL-8, IL-1b, M-CSF and GM-CSF expression in vascular smooth muscle cells.…”

Breviscapine inhibits high glucose-induced proliferation and migration of cultured vascular smooth muscle cells of rats via suppressing the ERK1/2 MAPK signaling pathway

“…Rupture of an atherosclerotic plaque may result in myocardial infarction, stroke or peripheral vascular disease [22,23] . Atheroma formation involves endothelial damage, oxidized low density lipoprotein (LDL) infiltration, macrophage activation, collagen deposition, a change in the phenotype of VSMCs, as well as an increase in proliferative and migratory capability of VSMCs [4,5,24] . Previous studies have indicated that hyperglycemia is an important causative factor in the development of diabetic atherosclerosis, and high glucose levels appeared to be an important contributor to the functional impairment of VSMCs [2,5,25,26] .…”

“…Many cytokines, such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), interferon γ (IFN γ) and monocyte chemotactic protein 1 (MCP-1), are secreted, which contributes to furthering the process of atherosclerosis [4][5][6] .…”

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…Additionally, NGF and furin can be detected in rodent arteries and human proliferating VSMCs [90]. Proliferating VSMCs play a critical role in the atherosclerotic initiation and progression by influencing growth factor/cytokine synthesis and ECM production in the arterial wall [91]. Inhibition of furin leads to the enhanced proNGF and decreased b-NGF secretion, causing apoptosis, instead of migration, of proliferating VSMCs.…”