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Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression
Stephane Potteaux, … , Mary G. Sorci-Thomas, Gwendalyn J. Randolph
Stephane Potteaux, … , Mary G. Sorci-Thomas, Gwendalyn J. Randolph
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):2025-2036. https://doi.org/10.1172/JCI43802.
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Research Article Vascular biology Article has an altmetric score of 15

Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe–/– mice during disease regression

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Abstract

Experimental models of atherosclerosis suggest that recruitment of monocytes into plaques drives the progression of this chronic inflammatory condition. Cholesterol-lowering therapy leads to plaque stabilization or regression in human atherosclerosis, characterized by reduced macrophage content, but the mechanisms that underlie this reduction are incompletely understood. Mice lacking the gene Apoe (Apoe–/– mice) have high levels of cholesterol and spontaneously develop atherosclerotic lesions. Here, we treated Apoe–/– mice with apoE-encoding adenoviral vectors that induce plaque regression, and investigated whether macrophage removal from plaques during this regression resulted from quantitative alterations in the ability of monocytes to either enter or exit plaques. Within 2 days after apoE complementation, plasma cholesterol was normalized to wild-type levels, and HDL levels were increased 4-fold. Oil red O staining and quantitative mass spectroscopy revealed that esterified cholesterol content was markedly reduced. Plaque macrophage content decreased gradually and was 72% lower than baseline 4 weeks after apoE complementation. Importantly, this reduction in macrophages did not involve migratory egress from plaques or CCR7, a mediator of leukocyte emigration. Instead, marked suppression of monocyte recruitment coupled with a stable rate of apoptosis accounted for loss of plaque macrophages. These data suggest that therapies to inhibit monocyte recruitment to plaques may constitute a more viable strategy to reduce plaque macrophage burden than attempts to promote migratory egress.

Authors

Stephane Potteaux, Emmanuel L. Gautier, Susan B. Hutchison, Nico van Rooijen, Daniel J. Rader, Michael J. Thomas, Mary G. Sorci-Thomas, Gwendalyn J. Randolph

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Figure 3

Analysis of migratory egress from atherosclerotic plaques in Apoe–/– mice following apoE complementation.

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Analysis of migratory egress from atherosclerotic plaques in Apoe–/– mic...
(A) Diagram depicts experimental design in which the Ly-6Clo monocytes of mice were labeled with beads in the blood before the mice served as transplant donors in a surgical model of regression. (B) Quantification of the number of beads per cross section of the aortic arch before (baseline) and after plaque regression in WT transplant recipients. Data were pooled from 3 independent experiments; n = 5 in the baseline group, n = 7 in the WT recipient group. Difference from baseline is significant, P < 0.01. (C) Experimental design to study migratory egress from plaques of Apoe–/– mice after apoE complementation. (D) Quantification of bead number in aortic sinus plaques (blue lines) or aortic arch (lesser curvature; red lines) after Ly-6Chi (upper graph; n = 5–7 mice per data point) or Ly-6Clo (lower graph; n = 10–16 mice per data point) monocytes were initially labeled in the blood. (E) Microphotograph of beads (green particles, some indicated by arrows) localized within an aortic arch plaque 4 weeks after labeling in the control group. Non-overlapping ORO (red) and DAPI (blue) staining reveals necrotic core. Data represent mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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