Absence of the Vitamin D Receptor Inhibits Atherosclerotic Plaque Calcification in Female Hypercholesterolemic Mice

Epidemiological and clinical data suggest adverse cardiovascular outcomes with respect to vitamin D deficiency. Here, we explored the effects of vitamin D in atherosclerotic plaque calcification in vivo by utilizing vitamin D receptor ( Vdr )‐deficient mice in an Apoe −/− background. Animals were fed a high‐fat diet (HFD) for either 12 or 18 weeks and then examined for atherosclerotic plaque development. In order to prevent calcium deficiency, Vdr −/− and Apoe −/− ; Vdr −/− animals were fed a high‐calcium rescue diet prior to initiation of the HFD feeding and supplemented with high‐calcium water during HFD feeding. Although calcium supplementation improved bone mass in Vdr −/− and Apoe −/− ; Vdr −/− mice, neither strain was fully rescued. Systemic inflammatory responses observed in the absence of VDR were exaggerated in Apoe −/− mice. Whereas, hyperlipidemic profiles seen in Apoe −/− mice were ameliorated in the absence of VDR. Micro‐computed tomography (µCT) analysis revealed that six out of eight Apoe −/− animals developed atherosclerotic plaque calcification following 12 weeks of HFD feeding and 100% of the mice developed plaque calcification after 18 weeks. In contrast, although atherosclerotic lesions were evident in Apoe −/− ; Vdr −/− mice at 12 and 18 weeks of HFD challenge, none of these animals developed plaque calcification at either time point. The active vitamin D hormone, 1,25(OH) 2 D 3 likely increased calcification in aortic smooth muscle cells perhaps by directly modulating expression of Alpl , Rankl , and Opg . Our data suggest that the absence of VDR inhibits atherosclerotic plaque calcification in hypercholesterolemic Apoe −/− mice, providing additional insight into the role of vitamin D in atherosclerotic plaque calcification. J. Cell. Biochem. 118: 1050–1064, 2017. © 2016 Wiley Periodicals, Inc.