Natriuretic Peptide Receptor 2 Locus Contributes to Carotid Remodeling.

Background Carotid artery intima/media thickness (IMT) is a hallmark trait associated with future cardiovascular events. The goal of this study was to map new genes that regulate carotid IMT by genome-wide association. Methods and Results We induced IMT by ligation procedure of the left carotid artery in 30 inbred mouse strains. Histologic reconstruction revealed significant variation in left carotid artery intima, media, adventitia, external elastic lamina volumes, intima-to-media ratio, and (intima+media)/external elastic lamina percent ratio in inbred mice. The carotid remodeling trait was regulated by distinct genomic signatures with a dozen common single-nucleotide polymorphisms associated with left carotid artery intima volume, intima-to-media ratio, and (intima+media)/external elastic lamina percent ratio. Among genetic loci on mouse chromosomes 1, 4, and 12, there was natriuretic peptide receptor 2 (), a strong candidate gene. We observed that only male, not female, mice heterozygous for a targeted deletion () exhibited defective carotid artery remodeling compared with wild-type () littermates. Fibrosis in carotid IMT was significantly increased in males compared with females or mice. We also detected decreased expression in human atherosclerotic plaques, similar to that seen in studies in mice. Conclusions We found that components of carotid IMT were regulated by distinct genetic factors. We also showed a critical role for in genetic regulation of vascular fibrosis associated with defective carotid remodeling.