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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

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 1

Kinetics of changes within Apoe–/– plaques following apoE complementation.

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Kinetics of changes within Apoe–/– plaques following apoE complementatio...
Apoe–/– mice were fed a HFD for 9 weeks before establishment of a baseline group or starting treatment with ad-hApoE3 or ad-Empty vector. The evolution of changes within plaque after 1, 2, or 4 weeks following adenoviral infection was characterized. (A) Total cholesterol measurements. Dashed line depicts the values obtained from age- and sex-matched C57BL/6 Apoe+/+ mice. (B) The plasma lipoprotein profile as a function of time following apoE complementation. (C) Lesion area was measured on 8-μm sections at 48-μm intervals, starting from the initiation of valves. (D) Macrophage area was quantified by CD68+ area and normalized to the average CD68+ area from the corresponding baseline group lesions. (E) Representative photomicrographs of CD68+ staining in sections of the aortic sinus of each experimental group. Red, CD68; blue, DAPI. Original magnification, ×50. (F) Neutral lipid area within lesions was quantified by ORO staining within each treatment group over time; the dashed line refers to baseline values obtained in Apoe–/– mice after 9 weeks of HFD feeding. (G and H) Total, free, and esterified cholesterol mass analysis at baseline or 14 days after apoE complementation normalized to wet weight of tissue (G) or tissue protein content (H) from 7–8 mice per group. Data represent mean ± SEM, except in A, which depicts mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. Results are compiled from 3 independent experiments with 5–8 animals per group per experiment.

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

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