Abstract 183: Differences in Genetic Regulation of Carotid Stenosis and Thickening in Mice
Introduction Most clinical and experimental studies are focused on the artery wall using a carotid intima-media thickening (IMT) phenotype. In physiological remodeling increases in IMT are coupled with increased arterial dimensions that preserve arterial blood flow. In contrast, pathological remodeling results in arterial stenosis. The goal of this study was to investigate genetic mechanisms of the carotid stenosis in inbred mice. Methods and Results We ligated external and internal branches of the left carotid artery, leaving the occipital artery patent to induce carotid IMT in mice. We evaluated flow-induced carotid remodeling in 9-12 week old males of 30 inbred mouse strains (n=270). Relative reductions in the left carotid blood flow were very similar among the mouse strains (Mean+SD= -86+7%) after two weeks after ligation. All animals were perfusion fixed with formalin and carotid arteries were stained with hematoxylin and eosin. There was less than 2-fold variation in carotid traits in controls. However, ligation resulted in a greater variation of carotid IMT (~6-fold) compared to carotid stenosis (~3-fold). The highest carotid IMT values were in SEA/GnJ, while the lowest IMT was in C3H/HeJ mice. Carotid stenosis was >60% in SEA/GnJ and SJL/J strains. There was significant correlation (R 2 =0.40) between carotid stenosis and IMT across 30 strains. We performed genome-wide association by using Efficient Mixed Model Association method for carotid traits in 30 inbred mice. Comparable numbers of genetic loci were associated with carotid IMT and stenosis after ligation. However, none of these loci overlap between the carotid stenosis and carotid IMT. Conclusions We found that major genetic modifiers for carotid stenosis are different from those that control carotid IMT. Our data also suggest that identification of mechanisms that determine carotid stenosis is difficult through studies on the carotid IMT.