Potential impact of the steroid hormone, vitamin D, on the vasculature.

The role of vitamin D in the cardiovascular system is complex because it regulates expression of genes involved in diverse metabolic processes. Although referred to as a vitamin, it is more accurately considered a steroid hormone, because it is produced endogenously in the presence of ultraviolet light. It occurs as a series of sequentially activated forms, here referred to as vitamin D-hormones. A little-known phenomenon, based on pre-clinical data, is that its biodistribution and potential effects on vascular disease likely depend on whether it is derived from diet or sunlight. Diet-derived vitamin D-hormones are carried in the blood, at least in part, in chylomicrons and lipoprotein particles, including low-density lipoprotein. Since low-density lipoprotein is known to accumulate in the artery wall and atherosclerotic plaque, diet-derived vitamin D-hormones may also collect there, and possibly promote the osteochondrogenic mineralization associated with plaque. Also, little known is the fact that the body stores vitamin D-hormones in adipose tissue with a half-life on the order of months, raising doubts about whether the use of the term "daily requirement" is appropriate. Cardiovascular effects of vitamin D-hormones are controversial, and risk appears to increase with both low and high blood levels. Since low serum vitamin D-hormone concentration is reportedly associated with increased cardiovascular and orthopedic risk, oral supplementation is widely used, often together with calcium supplements. However, meta-analyses show that oral vitamin D-hormone supplementation does not protect against cardiovascular events, findings that are also supported by a randomized controlled trial. These considerations suggest that prevalent recommendations for vitamin D-hormone supplementation for the purpose of cardiovascular protection should be carefully reconsidered.

Regulation of calcific vascular and valvular disease by nuclear receptors.

PURPOSE OF REVIEW: This review addresses recent developments in studies of lipid regulation of calcific disease of arteries and cardiac valves, including the role of nuclear receptors. The role of lipid-soluble signals and their receptors is timely given the recent evidence and concerns that lipid-lowering treatment may increase the rate of progression of coronary artery calcification, which has been long associated with increased cardiovascular risk. Understanding the mechanisms will be important for interpreting such clinical information. RECENT FINDINGS: New findings support regulation of calcific vascular and valvular disease by nuclear receptors, including the vitamin D receptor, glucocorticoid receptor, nutrient-sensing nuclear receptors (liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors), and sex hormone (estrogen and androgen) receptors. There were two major unexpected findings: first, vitamin D supplementation, which was previously believed to prevent or reduce vascular calcification, showed no cardiovascular benefit in large randomized, controlled trials. Second, both epidemiological studies and coronary intravascular ultrasound studies suggest that treatment with HMG-CoA reductase inhibitors increases progression of coronary artery calcification, raising a question of whether there are mechanically stable and unstable forms of coronary calcification. SUMMARY: For clinical practice and research, these new findings offer new fundamental mechanisms for vascular calcification and provide new cautionary insights for therapeutic avenues.

Interactive and Multifactorial Mechanisms of Calcific Vascular and Valvular Disease.

Calcific vascular and valvular disease (CVVD) is widespread and has major health consequences. Although coronary artery calcification has long been associated with hyperlipidemia and increased mortality, recent evidence suggests that its progression is increased in association with cholesterol-lowering HMG-CoA reductase inhibitors ('statins') and long-term, high-intensity exercise. A nationwide trial showed no cardiovascular benefit of vitamin D supplements. Controversy remains as to whether calcium deposits in plaque promote or prevent plaque rupture. CVVD appears to occur through mechanisms similar to those of intramembranous, endochondral, and osteophytic skeletal bone formation. New evidence implicates autotaxin, endothelial-mesenchymal transformation, and microRNA and long non-coding RNA (lncRNA) as novel regulatory factors. New therapeutic options are being developed.

Steroid Hormone Vitamin D: Implications for Cardiovascular Disease.

Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.

Vitamin D and osteogenic differentiation in the artery wall.

Vascular calcification is widespread, particularly in patients with chronic kidney disease, who receive, among other treatments, active vitamin D supplements. Emerging evidence indicates that vascular calcification is a regulated process that resembles embryonic endochondral osteogenesis, involving osteoblastic differentiation of vascular smooth muscle cells. In experimental animal models, high dosages of vitamin D consistently promote vascular calcification. In particular, the vitamin D-fed rat is frequently used as a model to assess putative regulators of calcific vasculopathy. The artery wall calcification in these animals most likely results from multiple mechanisms involving systems physiology of the complex, bone-vascular-renal-endocrine axis. Genetically engineered mice with upregulated vitamin D signaling pathways have also shed light on the molecular intermediaries, including fibroblast growth factor-23 and transcriptional intermediary factor 1-alpha. In contrast to the studies of animals, studies of humans show that vitamin D has an inverse relationship or little effect. This difference between in vitro and in vivo findings is most likely, again, due to the complex, systemic feedback regulatory mechanisms that control calcium-phosphate metabolism. Recent epidemiologic evidence suggests that there is a narrow range of vitamin D levels in which vascular function is optimized. Levels above or below this range seem to confer a significant increase in risk for cardiovascular disease. There is some evidence to suggest that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise interesting questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk.