Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice
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
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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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 4

Lymphatic vessel distribution in the mouse aorta and aortic sinus.

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Lymphatic vessel distribution in the mouse aorta and aortic sinus. (A) T...
(A) The descending aorta is seen through its autofluorescence in the green channel. Vessels staining positively for podoplanin and LYVE-1 are seen on the adventitial side of the aorta, weaving in and out of adjacent adipose tissue. These vessels lack smooth muscle actin (SMA) coverage, though some nearby blood vessels are positive. LYVE-1+ SMA– lymphatic vessels are absorptive lymphatic capillaries, rather than lymphatic collecting vessels. (B and C) LYVE-1 staining in the region of the aortic arch. Arrows point to a lymphatic capillary along the lesser curvature; arrowheads point out lymphatic capillaries near arteries that branch off the arch. (D) Cross-sectional analysis of the aortic sinus in an Apoe–/– mouse reveals lymphatic vessels under the areas where plaque typically develops. (E) Both WT littermates and Chy mice develop lymphatic vessels in the aorta as depicted in these cross sections of the aortic sinus.