Dietary Vitamin D Inadequacy Accelerates Calcification and Osteoblast-Like Cell Formation in the Vascular System of LDL Receptor Knockout and Wild-Type Mice

Abstract

Vitamin D insufficiency is highly associated with cardiovascular morbidity and mortality. We have demonstrated enhanced vascular calcification in LDL receptor knockout (LDLR(-/-)) mice fed a diet low in vitamin D. This study aimed to investigate the impact of a diet low in vitamin D on vascular calcification in wild-type (WT) mice lacking atherosclerotic plaques and the effects of a persistent and discontinuous vitamin D insufficiency on atherosclerotic plaque composition in LDLR(-/-) mice. The study was performed with 4-wk-old male WT and LDLR(-/-) mice that were fed a normal calcium/phosphate Western diet (210 g/kg fat, 1.5 g/kg cholesterol) containing either adequate (+D; 1000 IU/kg) or low (-D; 50 IU/kg) amounts of vitamin D-3 for 16 wk. Four groups of LDLR(-/-) mice received 1 of the 2 diets for additional 16 wk (total 32 wk) and were compared with mice fed the diets for only 16 wk. WT and LDLR(-/-) mice that were fed the -D diet for 16 wk tended to develop more calcified spots in the aortic valve than mice fed the +D diet (+50% and +56%, respectively; P < 0.10). In LDLR(-/-) mice, the extent of calcification increased from week 16 to week 32 and was higher in the -D than in the +D group (P < 0.05). The calcification, owing to the -D diet, was accompanied by highly expressed osteoblast differentiation factors, indicating a transdifferentiation of vascular cells to osteoblast-like cells. Feeding the +D diet subsequent to the -D diet reduced the vascular calcification (P < 0.05). LDLR(-/-) mice fed the -D diet for 32 wk had higher plaque lipid depositions (+48%, P < 0.05) and a higher expression of cluster of differentiation 68 (+31%, P < 0.05) and tumor necrosis factor α (+134%, P < 0.001) than the +D group. Collectively, the findings imply low vitamin D status as a causal factor for vascular calcification and atherosclerosis.

Association between circulating 25-hydroxyvitamin D levels and medication use in patients scheduled for cardiac surgery

“…There is evidence from experimental studies that important cardiovascular risk factors such as vascular calcification, foam cell formation and macrophage cholesterol uptake may be suppressed by adequate vitamin D supply [5,6]. Deficient and insufficient vitamin D status, i.e.…”

MICS, an easily ignored contributor to arterial calcification in CKD patients

“…In addition, some micronutrient deficiencies may promote AC via this mechanism. Feeding mice with low vitamin D for 16 wk, Schmidt et al (89) observed more calcified spots in the aortic valve than those given adequate vitamin D, accompanied by higher expressions of BMP2 and Runx2. Similarly, in animal VSMCs calcification models, administration of Mg dose-dependently decreased expressions of BMP2, osteocalcin, and ALP, leading to amelioration of VSMCs calcification (44,70).…”

Cardiovascular Calcification and Bone: A Comparison of The Effects of Dietary and Serum Calcium, Phosphorous, Magnesium and Vitamin D

“…There are no human intake studies with respect to CV calcification, probably because dietary vitamin D provides only a relatively small contribution to serum 25(OH)D. Animal studies, however, show that high vitamin D intake can induce CV calcification and impair endothelial function 128,129 but they also show that a vitamin D deficient diet can induce an increase in calcified lesions [130][131][132] , indicating that both excess and deficiency are detrimental. Several epidemiological studies measuring serum 25(OH)D demonstrate an absence of association with presence or extent of CAC, MAC, cIMT, degree of carotid stenosis or mean arterial pressure 22,[133][134][135] , although patients with calcific aortic stenosis 136 and poor coronary collateral circulation 137 140 and with the calcification score in peripheral arterial disease 27 .…”