Abstract 17: Reverse Cholesterol Transport Relies on a Functional Lymphatic Network
Introduction: HDL accepts free cholesterol from cells within extravascular tissues and transports it to the liver for excretion. Little is known about how HDL-C leaves such tissues to reach the blood. HDL-C is found in lymph, but it is unclear if lymphatics are critical for mobilization of HDL-C from tissues.
Methods & Results: We employed models of disrupted lymphatic drainage--one a surgical resection of lymphatics in the mouse tail and the other a genetic lack of skin lymphatics due to a mutation in VEGFR3--to quantify the role of lymphatic vessels in movement of HDL-C out of skin to plasma. We implanted bone marrow macrophages loaded with [3H]-cholesterol in skin sites and then quantified [3H]-cholesterol in plasma, liver, and feces. [3H]-cholesterol movement into plasma was reduced by 80% in both models of disrupted lymphatics, and this result was unaffected by conditions of a leaky blood vessels. To ensure that this reduction reflected events between efflux and appearance of cholesterol in plasma rather than altered macrophage cholesterol efflux, we substituted [3H]-cholesterol-loaded macrophages with congenic macrophages loaded with a fluorescently modified cholesterol compound that allowed us to monitor ABCA1/ABCG1-dependent efflux from individual macrophages in the same assays and models. Flow cytometric analysis of bodipy-cholesterol-loaded macrophages retrieved from injection sites revealed similar efflux in mice lacking functional lymphatics as in controls.
Conclusions: Mobilization of HDL-C from extravascular tissues to plasma occurs through the lymphatic vasculature. Recent studies show that transport through lymphatic vessels is compromised by hypercholesterolemia. Hypercholesterolemia-induced impairments in lymphatic function may retard clearance of cholesterol from extravascular tissues, possibly including atherosclerotic plaques.
- © 2012 by American Heart Association, Inc.