Rapid restoration of normal endothelial functions in genetically hyperlipidemic mice by a synthetic mediator of reverse lipid transport

Endothelial dysfunction is a major pathophysiological consequence of hyperc holesterolemia and other conditions. We examined whether a synthetic mediat or of lipid transport from peripheral tissues to the liver (ie, the "revers e" pathway) could restore normal endothelial function in vivo. Using assays of macrovascular and microvascular function, we found that genetically hyp ercholesterolemic 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 re verse 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 c oncentrations of cholesterol-rich atherogenic lipoproteins during the treat ment. Our results indicate that dysfunctional macrovascular and microvascul ar endothelium in apolipoprotein E knockout mice can recover relatively qui ckly in vivo and that accelerated reverse lipid transport may be a useful t herapy.