Induction of rapid atherogenesis by perivascular carotid collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice

Background-Perivascular collar placement has been used as a means for local ized atherosclerosis induction in a variety of experimental animal species. In mice, however, atherosclerosis-like lesions have thus far not been obta ined by this method. The aim of this study was the development of a mouse m odel of rapid, site-controlled atherogenesis. Methods and Results-Silastic collars were placed around the carotid arterie s of apolipoprotein E-deficient (apoE-/-) and LDL receptor-deficient (LDLr- /-) mice. The development of collar-induced lesions was found to occur pred ominantly in the area proximal to the collar and to be dependent on a high- cholesterol diet, Lesions were evident in apoE-/- mice after 3 weeks and in LDLr-/- mice after 6 weeks and were overtly atherosclerotic in appearance. Lumen stenosis reached 85% in apoE-/- mice and 61% in LDLr-/- mice 6 weeks after collar insertion, Expression levels of intercellular adhesion molecu le-1 and vascular cell adhesion molecule-1 were increased both proximal and distal to the collar, whereas endothelial nitric oxide synthase expression was downregulated at the proximal site, Conclusions-We propose that this model of collar-induced acceleration of ca rotid atherogenesis is of hemodynamic cause. It may serve as a substrate fo r sequential mechanistic studies concerned with the underlying cause and pa thogenesis of atherosclerosis. The rapidity of lesion development will also aid the efficient screening of new potentially antiatherogenic chemical en tities and the evaluation of therapies with limited duration of effectivene ss, such as adenoviral gene therapy.