Accelerated atherosclerosis by placement of a perivascular cuff and a cholesterol-rich diet in ApoE*3Leiden transgenic mice

Intimal hyperplasia after vascular injury is usually studied in animal mode ls with healthy, normocholesterolemic animals. Here, we assess the effect o f diet-induced hypercholesterolemia on the induction of intimal hyperplasia in ApoE*3Leiden mice. A nonconstrictive polyethylene cuff was placed aroun d the femoral artery of ApoE3*Leiden mice fed a highly cholesterol-rich die t, a mildly cholesterol-rich diet, or a chow diet for 4 weeks. Diets were c ontinued after cuff placement until euthanization. At several time points ( 1 to 14 days), mice were euthanized and the intimal hyperplasia in the cuff ed arteries was analyzed. In mice fed a chow diet, a 2- to 4-cell-layer-thi ck intima, predominantly consisting of ar smooth muscle cell actin-positive cells, was observed after 14 days. A mildly choresterol-rich diet (mean pl asma-cholesterol level, 10.5 mmol/L) resulted in a 2.7-fold increase of tot al intimal area, and a highly cholesterol-rich diet (mean plasma cholestero l level 28.6 mmol/L), in a 7.8-fold increase. In the high-cholesterol group , the intima consisted predominantly of Lipid-loaded foam cells and alpha s mooth muscle cell actin-positive cells. Foam cell accumulation could be obs erved by as early as 3 days, resulting in a near-total occlusion of the lum en after 14 days. Hypercholesterolemia resulted in a rapid, cholesterol-dep endent induction of foam cell-rich intimal hyperplasia in cuffed femoral ar teries of ApoE*3Leiden mice. In conclusion, the present data show that the combination of a local (cuff placement) and a systemic (hypercholesterolemi c) risk factor of atherosclerosis results in a rapid induction (within 14 d ays) of atherosclerotic-like lesions in ApoE*3Leiden mice.