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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1033.)
© 2000 American Heart Association, Inc.

Vascular Biology

Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport

Presented as a preliminary report at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-732–I-733).

Kevin Jon Williams; Rosario Scalia; Kirstin D. Mazany; Wendi V. Rodrigueza; Allan M. Lefer

From the Departments of Medicine (K.J.W., K.D.M., W.V.R.) and Physiology (R.S., A.M.L.), Thomas Jefferson University, Philadelphia, Pa.

Abstract—Endothelial dysfunction is a major pathophysiological consequence of hypercholesterolemia and other conditions. We examined whether a synthetic mediator of lipid transport from peripheral tissues to the liver (ie, the "reverse" pathway) could restore normal endothelial function in vivo. Using assays of macrovascular and microvascular function, we found that genetically hypercholesterolemic apolipoprotein E knockout mice exhibited key endothelial impairments. Treatment of the mice for 1 week with daily intravenous bolus injections of large "empty" phospholipid vesicles, which accelerate the reverse pathway in vivo, restored endothelium-dependent relaxation, leukocyte adherence, and endothelial expression of vascular cell adhesion molecule-1 to normal or nearly normal levels. These changes occurred despite the long-standing hyperlipidemia of the animals and the persistence of high serum concentrations of cholesterol-rich atherogenic lipoproteins during the treatment. Our results indicate that dysfunctional macrovascular and microvascular endothelium in apolipoprotein E knockout mice can recover relatively quickly in vivo and that accelerated reverse lipid transport may be a useful therapy.

Key Words: cell adhesion molecules • endothelium-derived factors • hypercholesterolemia • leukocytes • vasodilation

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