Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice

Martel, C. et al. (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. Journal of Clinical Investigation, 123(4), pp. 1571-1579. (doi: 10.1172/JCI63685)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Platt, Dr Andrew
• Authors: Martel, C., Li, W., Fulp, B., Platt, A.M., Gautier, E.L., Westerterp, M., Bittman, R., Tall, A.R., Chen, S., Thomas, M.J., Kreisel, D., Swartz, M.A., Sorci-Thomas, M.G., and Randolph, G.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• Published Online: 25 March 2013
• Copyright Holders: Copyright © 2013 American Society for Clinical Investigation
• First Published: First published in Journal of Clinical Investigation 123(4):1571-1579
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher