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(Circulation Research. 2002;91:577.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Accelerated Atherosclerosis and Calcification in Vein Grafts

A Study in APOE*3 Leiden Transgenic Mice

J.H.P. Lardenoye, M.R. de Vries, C.W.G.M. Löwik, Q. Xu, C.R. Dhore, J.P.M. Cleutjens, V.W.M. van Hinsbergh, J.H. van Bockel, P.H.A. Quax

From the Gaubius Laboratory TNO-PG (J.H.P.L., M.R.d.V., V.W.M.v.H., P.H.A.Q.), Leiden, the Netherlands; Leiden University Medical Center (J.H.P.L., C.W.G.M.L., J.H.v.B.), Leiden, The Netherlands; The Institute for Biomedical Aging Research (Q.X.), Innsbruck, Austria; and the Department of Pathology (C.R.D., J.P.M.C.), Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands.

Correspondence to Dr P.H.A. Quax, Gaubius Laboratory TNO-PG, PO Box 2215, 2301 CE Leiden, The Netherlands. E-mail PHA.Quax{at}pg.tno.nl

Vein grafts fail due to development of intimal hyperplasia and accelerated atherosclerosis. Many murine genetic models in which genes are overexpressed, deleted, or mutated have been introduced recently. Therefore, mouse models are very well suited to dissect the relative contribution of different genes in the development of accelerated atherosclerosis. In the present study, we evaluated whether accelerated atherosclerosis in human vein grafts could be mimicked in hypercholesterolemic APOE*3 Leiden transgenic mice. Venous bypass grafting was performed in the carotid artery in APOE*3 Leiden mice fed either a standard chow diet or a high cholesterol–rich diet for 4 weeks. At several time points (0 hour to 28 days), mice were euthanized and the morphology of the vein grafts was analyzed. In normocholesterolemic mice, vein graft thickening up to 10-fold original thickness, predominantly consisting of -smooth muscle cell actin–positive cells, was observed after 28 days. In hypercholesterolemic mice, accelerated atherosclerosis with accumulation of lipid-loaded foam cells was observed within 7 days after surgery. This accelerated atherosclerosis progressed in time and resulted in significant increase in vein graft thickening up to 50 times original thickness with foam cell–rich lesions and calcification within 28 days after surgery. The atherosclerotic lesions observed in these murine grafts show high morphological resemblance with the atherosclerotic lesions observed in human vein grafts. This accelerated, diet-dependent induction of atherosclerotic-like lesions in murine vein grafts provides a valuable tool in evaluating the mechanisms of accelerated atherosclerosis and therapeutic interventions of vein graft disease.

Key Words: vein graft • mice • accelerated atherosclerosis

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