Abstract
Low levels of 25-hydroxy vitamin D (25(OH)D) are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR−/−) mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P<0.01). Data from LDL receptor knockout (LDLR−/−) mice that were fed western diet with either low (50 IU/kg), recommended (1,000 IU/kg), or high (10,000 IU/kg) amounts of vitamin D3 over 16 weeks revealed increasing plasma concentrations of 25(OH)D (P<0.001) with increasing intake of vitamin D, whereas levels of calcium and phosphorus in plasma and femur were not influenced by the dietary treatment. Mice treated with the low vitamin D diet had more calcified lesions and a higher expression of Msx2, Bmp2, and Runx2 in aortic roots than mice fed recommended or high amounts of vitamin D (P<0.001). Taken together, these findings indicate vitamin D deficiency as a risk factor for aortic valve and aortic vessel calcification and a stimulator of osteogenic key factor expression in these vascular areas.
Highlights
Vitamin D deficiency has become a widespread public health problem [1]
In the mouse experiments reported here, VDR knockout and diet-induced reduction of vitamin D status resulted in enhanced aortic valve and vascular calcification
The results obtained from the VDR2/2 mouse study further revealed that calcification seems to be independent from other vascular processes because aortic valves of VDR2/2 mice became significantly calcified despite any identifiable atherosclerotic plaques
Summary
Vitamin D deficiency has become a widespread public health problem [1]. Humans normally get vitamin D from sunlight exposure, from their diets or dietary supplements. Seasonal variations of ultraviolet (UV)-B light exposure, increasing indoor activities, and the frequent use of sunscreens are reasons for the low synthesis of cutaneous vitamin D. These people strongly depend on dietary sources of vitamin D. Recent data from vitamin D receptor knockout (VDR2/2) mice, an animal model that emulates vitamin D deficiency [11], revealed a far greater number of fibrotic lesions in the hearts of these mice compared to those of the wild-type mice [12]. In a mouse model of chronic kidney disease, activators of vitamin D receptor such as calcitriol and paricalcitrol were effective in protection against aortic calcification in dosages that normalize secondary hyperparathyoidism, whilst higher dosages stimulated aortic calcification [13]. The physiological impact of a lack of vitamin D, and a lack of its native form, as reflected by the 25hydroxy-vitamin D (25OHD) on vascular composition and atherosclerotic plaque development remains largely unexplored
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