image: Cross-section of advanced plaque from a diseased mouse blood vessel showing clusters of smooth muscle cells (red, blue, and yellow) and infiltrating cells of non-smooth muscle origin, such as macrophages (green). view more
Credit: Image credit: Leeper Lab.
A study identifies the role of smooth muscle cells in driving the formation of atherosclerotic plaques. Current treatments for atherosclerosis target risk factors such as hypertension and diabetes, partly because the precise roles of the underlying cells driving plaque formation remain unclear. Nicholas Leeper and colleagues combined mouse lineage-tracing experiments with analysis of data from banked human samples to uncover the key role in atherosclerosis of a proliferating group of vascular smooth muscle cells found near the necrotic core of plaques. The cells produce complement protein C3, which stimulates macrophages while driving the cells' own clonal expansion. Although the C3 protein identifies the cells as pathologic and flags them for clearance by resident macrophages, the cells escape immune surveillance likely due to signal-sensing defects in activated macrophages found in plaques. The authors found that activated macrophages express high levels of CD47--a molecular signature commonly used by cells to avoid phagocytosis--that might double as an appetite suppressor in macrophages. Building on that finding, the authors showed that tamping down CD47 restores the ability of activated macrophages to clear complement-coated target cells. Additionally, mice treated with an anti-CD47 antibody exhibited reduced clonal expansion of vascular smooth muscle cells and lowered circulating C3 levels, compared with control mice, suggesting reduced vascular inflammation. According to the authors, the findings suggest that highly proliferative smooth muscle cells carrying stem cell markers drive atherosclerotic plaque formation and represent viable therapeutic targets, similar to cancer stem cells.
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Article #20-06348: "Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade," by Ying Wang et al.
MEDIA CONTACT: Nicholas Leeper, Stanford University, Stanford, CA; e-mail: nleeper@stanford.edu
Journal
Proceedings of the National Academy of Sciences