Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice
Catherine Martel, … , Mary G. Sorci-Thomas, Gwendalyn J. Randolph
Catherine Martel, … , Mary G. Sorci-Thomas, Gwendalyn J. Randolph
Published March 25, 2013
Citation Information: J Clin Invest. 2013;123(4):1571-1579. https://doi.org/10.1172/JCI63685.
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Research Article

Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice

Abstract

Reverse cholesterol transport (RCT) refers to the mobilization of cholesterol on HDL particles (HDL-C) from extravascular tissues to plasma, ultimately for fecal excretion. Little is known about how HDL-C leaves peripheral tissues to reach plasma. We first used 2 models of disrupted lymphatic drainage from skin — 1 surgical and the other genetic — to quantitatively track RCT following injection of [3H]-cholesterol–loaded macrophages upstream of blocked or absent lymphatic vessels. Macrophage RCT was markedly impaired in both models, even at sites with a leaky vasculature. Inhibited RCT was downstream of cholesterol efflux from macrophages, since macrophage efflux of a fluorescent cholesterol analog (BODIPY-cholesterol) was not altered by impaired lymphatic drainage. We next addressed whether RCT was mediated by lymphatic vessels from the aortic wall by loading the aortae of donor atherosclerotic Apoe-deficient mice with [2H]6-labeled cholesterol and surgically transplanting these aortae into recipient Apoe-deficient mice that were treated with anti-VEGFR3 antibody to block lymphatic regrowth or with control antibody to allow such regrowth. [2H]-Cholesterol was retained in aortae of anti–VEGFR3-treated mice. Thus, the lymphatic vessel route is critical for RCT from multiple tissues, including the aortic wall. These results suggest that supporting lymphatic transport function may facilitate cholesterol clearance in therapies aimed at reversing atherosclerosis.

Authors

Catherine Martel, Wenjun Li, Brian Fulp, Andrew M. Platt, Emmanuel L. Gautier, Marit Westerterp, Robert Bittman, Alan R. Tall, Shu-Hsia Chen, Michael J. Thomas, Daniel Kreisel, Melody A. Swartz, Mary G. Sorci-Thomas, Gwendalyn J. Randolph

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Figure 2

RCT in Chy mutant mice.

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RCT in Chy mutant mice. (A) [3H]-Cholesterol–loaded macrophages were inj...
(A) [3H]-Cholesterol–loaded macrophages were injected into the rear footpads of Chy mice or control littermates and tritium counts were assessed in plasma at 24 hours. Two background strains were compared; injected macrophages were made from the bone marrow of mice on the same background as the recipients into which they were injected. (B) Compiled tritium counts in plasma (black), liver (white), and feces (gray) from C57BL/6 Chy and WT mice euthanized 24 hours after [3H]-cholesterol–loaded macrophages were injected into the rear footpad. (C) Compiled tritium counts in plasma (black), liver (white), and feces (gray) from C57BL/6 Chy and WT mice euthanized 24 hours after [3H]-cholesterol–loaded macrophages were injected into the scapular area of the back skin. (D) Lipoprotein profiles in the plasma of Chy mice and littermate controls from the mixed or C57BL/6 backgrounds. Each panel represents 2 experiments performed with 5 replicates per experimental group (mean ± SEM). Statistics compared Chy mice with their control littermates in each case. *P < 0.05; **P < 0.01; ***P < 0.001.