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 (Npr2), a strong candidate gene. We observed that only male, not female, mice heterozygous for a targeted Npr2 deletion (Npr2+/−) exhibited defective carotid artery remodeling compared with Npr2 wild- type (Npr2+/+) littermates. Fibrosis in carotid IMT was significantly increased in Npr2+/− males com- pared with Npr2+/− females or Npr2+/+ mice. We also detected decreased Npr2 expression in human atherosclerotic plaques, similar to that seen in studies in Npr2+/− mice. CONCLUSIONS: We found that components of carotid IMT were regulated by distinct genetic factors. We also showed a critical role for Npr2 in genetic regulation of vascular fibrosis associated with defective carotid remodeling.