title: 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.affiliation: Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Martel
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Brian
authors.initials: B
authors.lastname: Fulp
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Platt
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Shu-Hsia
authors.initials: SH
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000637:transplantation; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D015870:Gene Expression; D007700:Kinetics; D042601:Lymphatic Vessels / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012850:Sinus of Valsalva / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D002784:Cholesterol; D040321:Vascular Endothelial Growth Factor Receptor-3