A critical reassessment of murine and rabbit models of atherosclerosis: focus on lesion progression and remodelling

Abstract

Background Experimental animal atherosclerosis models are frequently regarded as an adequate surrogate for human vascular disease. The external validity of these models should be approached critically.Objectives The current study provides a direct comparison of atherosclerosis progression in four different animal models: C57BL/6 apolipoprotein (apo) E-/- mice, C57BL/6 low density lipoprotein receptor deficient mice (LDLr/- mice), heterozygous LDL receptor deficient rabbits (LDLr+/- rabbits), and homozygous LDL receptor deficient rabbits (LDLr-/- rabbits). The main objective was to perform a longitudinal analysis of arterial remodelling and of the evolution of the medial area during atherosclerosis progression. Secondary objectives were to analyse sex differences in atherosclerosis progression and to determine intersite correlations.Results Progression of atherosclerosis in all models was accompanied by expansive (overcompensatory) remodelling leading not only to the absence of luminal narrowing but also to an increase of the absolute lumen size. Atherosclerosis progression in mice and rabbits is often accompanied by an increase of the medial area. Female mice are more susceptible or equally susceptible to atherosclerosis development compared to male mice notwithstanding lower plasma cholesterol levels. However, this sex difference was not reiterated in both rabbit models. Whereas cholesterol-fed LDLr/- mice show a moderate or strong correlation between the extent of advanced atherosclerosis in the aortic root and the brachiocephalic artery, no such correlation was observed in apo E-/- mice.Conclusion The extensive morphometric data in the current study provide a framework to critically reassess the potential and limitations of animal models of atherosclerosis.