Vitamin D and the endothelium: basic, translational and clinical research updates

Introduction and background: Vitamin D deficiency has been associated with cardiovascular diseases (CVDs) and its surrogate indicators such as endothelial dysfunction. It is an independent predictor of CVDs and all-cause mortality.

Methods: We review the updated literature surrounding vitamin D and the endothelium spanning molecular, translational and clinical studies including randomized controlled trials (RCTs). We review the possible actions of vitamin D on the quiescent and activated endothelium including lessons from animal models. We review the recent literature for association of Vitamin D deficiency with endothelial dysfunction and cardiovascular complications, and for clinical trials done to look at the effect of vitamin D supplementation on the endothelium and cardiovascular outcome.

Results and conclusion: Vitamin D deficiency is associated with endothelial dysfunction and cardiovascular diseases. Vitamin D stabilizes the quiescent endothelium, modulates certain stages of endothelial activation, and is involved in the repair of the damaged endothelium in vitro and in vivo. Twelve recent cross sectional studies, including 2086 subjects of varying ethnic groups, show an association between endothelial dysfunction and vitamin D deficiency. Yet 10 recent RCTs of vitamin D supplementation involving 824 subjects have failed to show significant improvements in endothelial function in the short term. So far, RCTs have not been able to confirm or refute the benefit of vitamin D supplementation on vascular mortality. Longer term randomized controlled trials using doses of vitamin D to optimize serum 25(OH)D concentrations to 20.0–40.0 ng/mL (50.0–100.0 nmol/L) or using vitamin D analogues with no calciotropic effects are needed to assess endothelial function and cardiovascular outcomes.

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Alex’s Notes: The review at hand looks at the effects of vitamin D on the endothelium – a complex endocrine and paracrine organ that plays a vital role in vascular health and disease. You may better recognize it better as the cells within blood and lymph vessels. Most cardiovascular risk factors such as elevated blood lipids, high blood pressure, hyperglycemia, and even smoking activate the endothelium to produce numerous inflammatory molecules. When these risk factors are chronic, the constant production of reactive oxygen species (ROS; free radicals) can overcome the natural antioxidant systems of the endothelium and lead to damage and disease.

It may seem odd to think that vitamin D, which is so famously known for its bone and calcium regulation could impact blood vessel health. But given how vitamin D improves strength, boosts athletic performance, and has an intimate relationship with obesity and muscle mass, a relationship to our blood vessels may actually not be so far-fetched. Before delving into this idea, however, it is prudent we establish a basic understanding of vitamin D. It is in essence a pseudo-hormone more so than a vitamin.

Vitamin D is synonymous with vitamin D3 (cholecalciferol), which is synthesized within our skin upon exposure to ultraviolet B (UVB) radiation. This is also the form that exists in some animal foods and is commonly supplemented. A very structurally similar compound is vitamin D2 (ergocalciferol), which is synthesized within plants but is far less effective than D3 in efficiency and should not be supplemented. Within 20-30 minutes of full-body sun exposure, 10,000 to 20,000 IU of vitamin D3 is produced, and maximum levels are reached in a few hours. At this point, the body has potent defense system to prevent toxicity – it converts vitamin D into other metabolites (tachysterol and then lumisterol) that will continue to accumulate with UVB exposure. These metabolites are then converted back into vitamin D during darkness, which is released into the bloodstream on a needs basis.

In other words, the skin not only stores the vitamin D it creates from sunlight, but also other metabolites that serve as a vitamin D reservoir so as to make toxicity naturally impossible. This reservoir has the added benefit of allowing the body a consistent supply of vitamin D during times of darkness, since the metabolites are easily converted back into vitamin D within the skin. The vitamin D is then bound to vitamin D binding proteins (DBP) and transported within the bloodstream to the liver where it is transformed into a more potent form – 25(OH)D or calcidiol.

This was known over three decades ago and is also a strong reason to consider topical vitamin D supplementation rather than oral, which can be toxic. Oral vitamin D supplements must be transported within chylomicrons rather than endogenous vitamin D, which is bound to DBPs. The result is that much is lost to peripheral tissues such as fat and skeletal muscle, which would explain the association between greater BMI and low serum 25(OH)D. However, that which does make it to the liver raises plasma 25(OH)D levels to concentrations that exceed DBP capacity, releasing free 25(OH)D into circulation where it enters cells to exert direct effects on gene expression. This is one reason why supplementation requires constant monitoring of serum 25(OH)D levels and why everyone is so variable in their response to supplementation.

25(OH)D is converted to 1,25(OH)2D3 in the kidneys, which interacts with vitamin D receptors (VDRs) located in up to 36 target organs, including the skin, endothelium, pancreas, prostate, intestine and immune system.  It has been estimated that the VDR can regulate the expression of as many as 500 of the approximately 20,488 genes in the human genome.

Getting back to the endothelium, maternal vitamin D deficiency has been demonstrated in rats to lead to hypertension, increased basal tone, and endothelial dysfunction from a developmental reduction in vitamin D, suggesting a role of vitamin D even during development. Its importance has been demonstrated in humans as well. Although no associations were found with cardiovascular markers, human maternal vitamin D deficiency was associated with lower muscle mass and greater insulin resistance in the offspring by nine years of age.

Interactions with endothelial VDRs increase nitric oxide production via phosphorylation of p38, Akt, and ERK. Vitamin D also acts as an antioxidant through other pathways and it has been demonstrated that deficient persons display elevated proinflammatory molecules. Overall, numerous clinical studies have associated vitamin D deficiency with higher oxidative stress, higher inflammation, and greater endothelial dysfunction. Accordingly, several clinical trials have examined whether vitamin D supplementation would benefit endothelial function. They all varied in length and mode of delivery, but the results are not encouraging and have not been able to confirm or refute the benefit of vitamin D supplementation on vascular mortality. That said, it was also shown that any improvement in vitamin D status improved expression of genes that have a wide variety of biological functions and that to maximize vitamin D's effect on gene expression may require even higher doses than 2000 IU of vitamin D3 daily.

Since a major molecule of blood vessel health is nitric oxide, it is interesting to note that the skin itself is a significant source of NO that is mobilized by sunlight. Hence, it is plausible that sunlight itself is cardioprotective by not only stimulating vitamin D synthesis, but also the synthesis of NO.


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