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 Table of Contents  
Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 127-138

Molecular mechanism of vasoprotective effects of Vitamin D

1 Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Ethiopia
2 Department of Biomedical Sciences, College of Public Health and Medical Sciences, Jimma University, Jimma, Oromia, Ethiopia

Date of Web Publication20-Jul-2018

Correspondence Address:
Mr. Leta Melaku
Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijhas.IJHAS_46_17

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Vitamin D is a prohormone which is converted into its active hormonal form 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in order to activate targeted genes to engender its biological actions. Through both 1,25(OH)2D3-dependent and 1,25(OH)2D3-independent Vitamin D receptor, it actions may involve more than one single receptor and ligand. Vitamin D plays important, pleiotropic role primarily in the maintenance of calcium and phosphate homeostasis by influencing the balance between bone resorption and formation. However, its influence goes far beyond the regulation of mineral homeostasis as diverse activities of Vitamin D assure through both genomic and nongenomic pathways, and it has a physiological value upon vascular health. It has been shown to protect against endothelial dysfunction, vascular smooth muscle cell proliferation and migration, and modulation of the immune system as well as the inflammatory response. In addition, vitamin D has been shown to have systemic effects on insulin resistance, dyslipidemia, and hypertension. Although some vitamin D is essential for cardiovascular health, excess may have detrimental effects, particularly on elastogenesis and inflammation of the arterial wall. This review explores the physiological role of vitamin D in vascular health protection.

Keywords: CVD, Metabolism, Vascular health, Vitamin D

How to cite this article:
Melaku L, Mossie A. Molecular mechanism of vasoprotective effects of Vitamin D. Int J Health Allied Sci 2018;7:127-38

How to cite this URL:
Melaku L, Mossie A. Molecular mechanism of vasoprotective effects of Vitamin D. Int J Health Allied Sci [serial online] 2018 [cited 2023 Jun 6];7:127-38. Available from: https://www.ijhas.in/text.asp?2018/7/3/127/237263

  Introduction Top

When Vitamin D was discovered in 1922 by McCollum, it was termed “D” because it was the fourth known vitamin.[1] It is, however, nowadays clear that Vitamin D and its metabolites should be rather classified as (pro-) hormones than as vitamins [2],[3] In humans, 80%–90% of required Vitamin D is derived by ultraviolet-B spectrum of sunlight-induced (wave length: 280–320 nm) Vitamin D production in the skin, and the remaining 10%–20% is provided from the nutritions (fatty fish, eggs, fortified dairy products, and mushrooms)[4],[5],[6],[7] Both Vitamins D produced in the skin (Vitamin D3) and/or obtained from food (Vitamin D2) are biologically inactives.[8] They requires two subsequent hydroxylations to gain its full hormonal activity.[8],[9] Initially, within hepatocytes by the 25α-hydroxylase or CYP2R1 then by another hydroxylase enzyme within kidney, CYP27B1 (1α– hydroxylase), they are converted to its biologically active form 1,25-dihydroxyvitamin D3 (1,25(OH)2D3).[8],[10] The recommended daily of Vitamin D intake ranges from 0 in those at low risk of osteoporosis to 15 g per day for those at high risk (65 years, dark skin, and restricted exposure to sunlight).[6],[11] Vitamin D receptors (VDRs) have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes.[12] Through genomic pathway, 1,25(OH)2D3 influences a number of genes relevant to the arterial wall, including vascular endothelial growth factor, matrix metalloproteinase Type 9, myosin, and structural proteins, such as elastin and Type I collagen [6],[13],[14],[15],[16] In addition to genomic pathway, by nongenomic pathway, it also has effect on arterial wall vascular smooth muscle cell (VSMC) migration through activation of phosphatidylinositol 3-kinase [6],[17],[18] [Figure 1]. In some studies as also confirmed, it improves endothelial function,[19],[20] regulates the growth and proliferation of VSMCs and cardiomyocytes,[12] and reduces the production of pro-inflammatory cytokines,[21] activity of the renin–angiotensin–aldosterone system, and parathyroid hormone (PTH) levels.[22] In one intervention study, supplementation with calcium and Vitamin D resulted in a substantial (9%) decrease in systolic blood pressure in elderly women.[23] It may also cause decreasing endothelial adhesion molecules, increasing nitric oxide production,[24] and reducing platelet aggregation.[25],[26] Other potential mechanisms linking Vitamin D to vascular health include the decrease in oxidative stress [20] and attenuation of nuclear factor-kappa B activation.[27]
Figure 1: Genomic and nongenomic responses to 1,25 dihydroxycholecalciferol

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Vitamin D deficiency (VDD) is also associated with higher circulating concentrations of matrix metalloproteinase-9 which controls vascular wall remodeling.[28] Low Vitamin D (<50 mol/L) is independently associated with incident CVD,[28] heart failure, and peripheral artery disease prevalence.[30] In conjunction with PTH, Vitamin D is responsible for the regulation of calcium and phosphate homeostasis. Moreover, low Vitamin D status is associated with a higher prevalence of vascular calcifications, bone and mineral disturbances, susceptibility to some infections, higher risk of autoimmune diseases, some malignancies, and many other complications.[2] In general, based on various studies, Vitamin D has a role in maintaining vascular health through both the direct action of the vitamin on blood vessel and the indirect actions on circulating hormone and calcium levels.[31]

  Regulation of Vitamin D Metabolism Top

PTH is the principal regulator of the renal synthesis of 1,25(OH)2D3. The primacy of PTH in the regulation of synthesis of 1,25(OH)2D3 is also well documented by both in vivo and in vitro studies using a wide variety of laboratory animals.[32],[33],[34] Dietary PO4 restriction also has been shown to stimulate renal 1α-hydroxylase activity as well as its messenger RNA. This action of PO4 is independent of PTH and is believed to be through a systemic hormone which is yet to be identified. However, it is conjectured that it may be one of the several newly discovered phosphaturic factors known collectively as phosphotonins (fibroblast growth factor-23).[35] Phosphotonins are currently thought to be regulators of circulating 1,25(OH)2D3 through their action on 1α-hydroxylase gene.[36] The gene expression of 24α-hydroxylase is enhanced by increasing PO4 level and decreasing PTH levels.[37] Thus, the 24α-hydroxylase gene is regulated in a reciprocal manner to the gene expression of 1α-hydroxylase [38],[39]

  Mechanism of Action of Vitamin D Top

The mechanism of action of the active form of Vitamin D3, 1,25(OH)2D3, is similar to that of other steroid hormones.[35] The intracellular mediator of 1,25(OH)2D3 function is VDR. 1,25(OH)2D3 binds stereospecifically to VDR, which is a high-affinity, low-capacity intracellular receptor that has extensive homology with other members of the superfamily of nuclear receptors including receptors of steroid and thyroid hormones and VDR functions as a heterodimer with the retinoid X receptor (RXR) for activation for Vitamin D target genes.[35] Once formed, the l, 25(OH)2D3-VDR-RXR heterodimeric complex interacts with specific DNA sequences (Vitamin D response elements [VDREs]) within the promoter of target genes, resulting in either activation or repression of transcription.[40],[41],[42],[43] In general, for activation of transcription, the VDRE consensus consists of two direct repeats of the hexanucleotide sequence GGGTGA separated by three nucleotide pairs.[35] The mechanisms involved in VDR-mediated transcription after binding of the 1,25(OH)2D3-VDR-RXR heterodimeric complex to DNA are now beginning to be defined.

TFIIB, several TATA-binding protein-associated factors (TAFs), as well as the p160 coactivators known also as steroid receptor activator-1,-2, and-3 (SRC-I, SRC-2, and SRC-3), which have histone acetylase activity have been reported to be involved in VDR-mediated transcription.[35] In addition to acetylation, methylation also occurs on core histones. Recent studies have indicated that cooperativity between histone methyltransferases and p160 coactivators may also play a fundamental role in VDR-mediated transcriptional activation.[44] VDR-mediated transcription is also mediated by the coactivator complex VDR-interacting protein (DRIP). This complex does not have HAT activity but rather functions, at least in part, through recruitment of RNA polymerase II. It has been suggested that the SRC/cAMP response element-binding protein (CBP) coactivator complex is recruited first for chromatin remodeling followed by the recruitment of the transcription machinery by the DRIP complex.[42],[45] In addition, a number of promoter-specific transcription factors including YY1 and CCAAT enhancer-binding proteins β and δ have been reported to modulate VDR-mediated transcription.[46],[47],[48] It has been suggested that cell- and promoter-specific functions of VDR may be mediated through differential recruitment of coactivators.[35]

  Role of Vitamin D in the Renin–angiotensin System Top

The first clinical studies suggesting an inverse relationship between calcitriol and renin levels were published two decades ago [49],[50],[51] and were recently confirmed in a large cohort study.[52] Several studies have indicated that serum levels of 1,25(OH)2D3 are inversely associated with blood pressure or plasma renin activity in normotensive and hypertensive patients.[49],[50],[53],[54],[55],[56] In an experimental study with wild-type mice, the research group of Li et al.[57] showed that inhibition of 1,25(OH)2D3 synthesis led to an increase in renin expression, accompanied by increased plasma angiotensin II levels, hypertension, and cardiac hypertrophy,[57] whereas 1,25(OH)2D3 injection led to renin suppression in the juxtaglomerular apparatus, independently of PTH and calcium metabolism.[4],[49],[58] The same group also demonstrated, in cell cultures, that 1,25(OH)2D3 directly suppressed renin gene transcription by means of a VDR-dependent mechanism.[4],[57] Elucidating this mechanism, a study found that 1,25(OH)2D3 suppressed renin gene expression in part by blocking the formation of the cyclic AMP response element [4],[49],[59] [Figure 2].
Figure 2: The effects of Vitamin D on the renin–angiotensin system. 1, 25-dihydroxyvitamin D suppresses renin gene expression, thereby inhibiting the renin–angiotensin system. ACE: Angiotensin-converting enzyme; H2O: Water; Na+: Sodium

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These data suggest that Vitamin D analogs and supplements may potentially be agents for controlling renin production and blood pressure.[4] Corroborating this hypothesis, Fryer et al.[60] evaluated the effects of paricalcitol and calcitriol on renin expression in C57/BL6 mice and showed that paricalcitol produces significant dose-dependent reductions in renin/GAPDH expression and calcitriol produced renin suppression.[49] In addition, Zhou et al.[61] demonstrated regulation of the renin–angiotensin system through supplementation of 1,25(OH)2D3 in 1α-hydroxylase knockout mice free of enzyme. On a molecular level, calcitriol binds to the VDR and subsequently blocks formation of the CRE-CREB-CBP complexes in the promoter region of the renin gene, reducing its level of expression [49],[59] Together, the associations found in clinical studies and the supporting mechanistic studies make it plausible that VDD could indeed contribute to an inappropriately activated renin–angiotensin–aldosterone system (RAAS), as a mechanism for progression of CKD and/or cardiovascular disease.[4] This may well be relevant for therapeutic purposes. Several lines of evidence indicate that persistent RAAS activity, either by incomplete pharmacologic blockade or related to the reactive rise in renin during therapy, can hamper its therapeutic efficacy.[4] This is suggested by the added antiproteinuric effect of renin inhibition to AT1-receptor blockade.[62] These findings hypothesize that treatment with a VDR agonist, on top of conventional RAAS-blockade, would give additional renoprotection through its negative regulation of renin.[4] In line with this notion, several experimental studies confirm that the renoprotective effects of vitamin are mediated at least in part through the suppression of renal renin expression.[49],[63],[64] In a recent randomized controlled trial (RCT), paricalcitol given in addition to RAAS blockade further reduces albuminuria compared with RAAS blockade alone in patients with diabetic nephropathy although it remains unclear whether this therapeutic benefit was obtained by an effect on renal renin activity.[49],[65] Vitamin D analogs may also have cardioprotective effects in association with suppression of renin in the kidney and heart.[66],[67] Whether paricalcitol reduces left ventricular hypertrophy in Stage III/IV CKD patients is currently under investigation in the PRIMO study (Clinical Trials.gov Identifier: NCT00497146).[4],[49] Interactions between Vitamin D and other RAAS components have been studied as well. Aldosterone acts through the mineralocorticoid receptor, which belongs to the same superfamily of nuclear receptors as VDR.[4]

Therefore, cross talk between these receptors and their agonists could potentially exist, but this has not been studied so far.[49] Mice that are genetically deficient for Klotho, a protein associated with downregulation of 1α-hydroxylase and thus limited production of calcitriol, show excessive levels of calcitriol but also hyperaldosteronism, which is similarly reversed by a Vitamin D-deficient diet [49],[68] Although these findings suggest a possible interaction between Vitamin D and aldosterone synthesis, it is uncertain whether hyperaldosteronism is a direct consequence of hypervitaminosis D. Data from in vitro studies do not support positive regulations of aldosterone synthesis by Vitamin D as treatment of cultured adrenocortical cells with calcitriol reduces aldosterone levels.[69] In VDR null mice, although there seems to be a trend toward increased aldosterone levels, the elevation is not significant as compared with wild-type mice,[70] which is in contrast with the strong downregulation of renal renin,[63] suggesting that the effect on aldosterone may in fact be through renin.[49] Treatment of spontaneous hypertensive rats with cholecalciferol also reduces plasma aldosterone levels, but here, also, a direct suppressive effect on renin transcription cannot be excluded.[4],[71]Vice versa, aldosterone may potentiate the effects of calcitriol, as demonstrated in cultured renal thick ascending limb cells.[72] In this study, calcitriol negatively regulates HCO3 absorption in the rat medullary thick ascending limb, which may contribute to net urine acid and/or calcium excretion.[49] Addition of aldosterone potentiated the effects of calcitriol through an Extracellular Signal Regulated Protein Kinase-dependent, nongenomic pathway.[4] This implicates that cross talk between mineralocorticoid receptor and VDR may indeed be present and requires further study.[5],[49] Whether Vitamin D modulates the expression of angiotensin II receptors is unknown. The only study on this subject reports that in adipocytes, Vitamin D downregulates expression of the AT1 receptor in a dose-dependent manner,[73] but, to our knowledge, these findings have never been replicated in other cell types.[4],[49]

  Role of Vitamin D in Peripheral Arterial Calcification Top

Arterial calcification is important because it has been shown to be a forerunner of cardiovascular events.[6] The molecular biology of arterial calcification will not be described in detail as it has been the subject of recent reviews.[74],[75],[76] However, the possible role of Vitamin D in arterial calcification will be discussed.[6],[74] There are two distinct patterns of arterial calcification: calcification of the media (Monckeberg's sclerosis, seen in aging, chronic renal failure, and diabetes) and calcification of the intima (seen in atherosclerosis).[6]

Intimal calcification has attracted considerable attention, particularly in the context of the prognostic significance of coronary artery and aortic arch calcification.[77],[78] However, most of the increase in arterial calcium with age is concentrated in the medial layer.[79] This medial calcification is not usually occlusive or associated with atherosclerotic plaque but is nevertheless a predictor of lower limb amputation and cardiovascular mortality.[6],[80],[81] Medial calcification also results in incompressible arteries and difficulty in measuring true ankle pressures, which can complicate the noninvasive diagnosis of peripheral arterial disease. An inverse relationship between serum 1,25(OH)2D3 levels and total (intimal and medial) coronary artery calcification has been reported.[6],[82],[83] This association may depend on medial calcification, whereas another study failed to demonstrate an association between intimal calcification and serum 1,25(OH)2D3 levels.[84] The significance of an inverse relationship between levels of 1,25(OH)2D3 and coronary calcification is uncertain, particularly as levels of 25(OH)D3 are a better indicator of Vitamin D status.[6],[85] There is increasing evidence of a paradoxical association between osteoporosis and vascular calcification.[86],[87],[88] The mechanisms underlying this association are beginning to be unraveled [89],[90],[91] and may account for the inverse association between coronary artery calcification and serum levels of 1,25(OH)2D3.[6],[82] Various inhibitors of bone resorption, including bisphosphonates (alendronate and ibandronate), osteoprotegerin, and an inhibitor of osteoclastic V-H-ATPase (SB 242784) have been shown to inhibit calcification of the arterial media in animal models.[89],[90],[92] Since none of these agents are known to act directly on the arterial smooth muscle cells, it has been proposed that arterial calcification is directly linked to bone resorption in this model.[6],[90] 1,25(OH)2D3 may, however, act directly on smooth muscle cells or osteoclast-like cells within the arterial wall.[93],[94] Medial calcification is common in diabetes and end-stage renal failure, both conditions being associated with peripheral arterial disease.[6] In renal failure, 1,25(OH)2D3 analogs are used to prevent secondary and tertiary hyperparathyroidism, and treatment with Vitamin D has been implicated in calcification of soft tissues, including the arterial wall.[6],[95] Recently, a large observational study has indicated that a selective VDR antagonist (paricalcitol) improves survival for renal failure patients, by 16% to 25%, in comparison to traditional calcitriol therapy.[6],[96]

In support of this finding, in vitro experiments show that VSMCs undergo calcification when treated with 1,25(OH)2D3 through a mechanism dependent on suppression of an endogenous inhibitor of calcification (PTH-related peptide) and PTH receptor signaling [93],[97] Hence, Vitamin D exposure may downregulate the paracrine mechanisms that, under normal circumstances, protect the vasculature from calcification. This has led to recent speculation that inflammation of the vascular adventitia with local synthesis of 1,25(OH)2D3 by macrophages could lead to medial calcification.[6],[98] 1,25(OH)2D3 through its interaction with VDR can induce the calcification of cultured arterial smooth muscle cells.[93] Apoptosis, which is well documented in atherosclerosis and after arterial injury, may provide an initial stimulus for calcification within the arterial wall.[99],[100] 1,25(OH)2D3 can induce cell cycle arrest and apoptosis in some normal and malignant cell types.[101],[102] Although 1,25(OH)2D3 has been shown to inhibit angiogenesis by induction of apoptosis, there is no direct evidence linking Vitamin D to peripheral arterial calcification through this mechanism.[6] Although adequate Vitamin D nutrition is essential for optimal vascular function,[103] both exogenous and endogenous 1,25(OH)2D3 are possible axes for the association. In contrast to endogenous Vitamin D, which is carried by circulating Vitamin D-binding protein, exogenous Vitamin D may be carried by lipoproteins.[104] This may facilitate accumulation of Vitamin D within atherosclerotic plaque and alter macrophage gene expression [6],[105],[106],[107]

  Role of Vitamin D in Peripheral Vascular Resistance Top

Although the evidence concerning Vitamin D exposure and hypertension is controversial, it is possible that Vitamin D influences vascular tone.[6] The single study that has investigated the short-term effect of Vitamin D on cardiovascular hemodynamics showed that Vitamin D caused rapid changes in patients with essential hypertension but not in controls.[74],[108],[109] In patients with essential hypertension, the cardiac output decreased by 15% within 2 h of intravenous administration of 1,25(OH)2D3 (0.2/kg). This was associated with transient smaller increases in pulse rate and mean blood pressure, suggesting that 1,25(OH)2D3 had a nongenomic effect to increase peripheral resistance.[6] This would be supported by an earlier report that indicated a correlation between calf vascular resistance, both before and during reactive hyperemia, with serum concentrations of 25(OH)D3 in hypertensive patients.[110]

The ability of 1,25(OH)2D3 to increase vascular resistance is supported by animal studies.[111] 1,25(OH)2D3 increases the sensitivity of resistance arteries to norepinephrine in hypertensive but not normotensive rats [112] and rapidly enhances arterial force generation by modulation of intracellular calcium concentration.[113],[114] Taken together, these studies suggest that hypertension induces or sensitizes putative plasma membrane VDRs which modulate intracellular calcium concentrations and hence resistance artery force generation. The identity of these plasma membrane receptors is obscure, as are the downstream kinase signaling cascades. In the absence of hypertension, these fast nongenomic responses have not been observed.[6] Even in the presence of hypertension, in the longer term, the fast nongenomic responses may be counteracted by the genomic effects of 1,25(OH)2D3 which may function to decrease vascular resistance. Likely, mechanisms include altered expression of myosin isoforms in resistance vessels.[6],[115] This would be consistent with the reported decrease of systolic blood pressure after 8 weeks of oral calcium and Vitamin D supplementation in the late winter.[6],[21]

  Role of Vitamin D in Inflammatory Vascular Disease Top

Several years ago, the hypothesis was elaborated that impaired synthesis of elastin in the walls of the aorta and other elastic or conduit arteries during fetal development was an initiating event in the pathogenesis of hypertension.[116] Since tropoelastin synthesis is known to be downregulated by Vitamin D, through a posttranscriptional mechanism,[13] excess Vitamin D during fetal development could cause the impaired synthesis of elastin discussed by Martyn and Greenwald.[116] Loss of medial elastin is a pathological hallmark of abdominal aortic aneurysm (AAA). This led to Norman elaborating a further hypothesis that excess Vitamin D consumption in early life led to the development of AAA in later life.[6],[117] The transportation of Vitamin D across the placenta is specifically enhanced during the last one-third of pregnancy (a period of maximal aortic elastin deposition).[118],[119] The neonate is dependent on stored Vitamin D because mammalian milk contains minimal Vitamin D.[120] This suggests that if maternal intake is excessive, then fetal and neonatal exposure will also be excessive.[6]

Although there are no clinical studies to support an association between increased maternal Vitamin D intake and impaired aortic elastogenesis, an experimental animal study demonstrated that exposure to increased Vitamin D in early life was associated with a reduction in elastin content and elastic lamellae number in the abdominal aorta.[121] The studies were not extended to investigate the possibility of aneurysm formation in aging rats.[6] Another pathological hallmark of AAA is inflammation.[122] Interestingly, there are recent scientific observations to support an important role for Vitamin D and its analogs on the immune system, particularly macrophages and T-lymphocytes expressing VDR, which could have important implications for both AAA and other peripheral arterial disease. The highest expression of VDR is in CD8 lymphocytes, with less expression in CD4 lymphocytes and macrophages, whereas B cells do not express VDR.[6] Moreover, VDR expression in CD8 cells increases in response to 1,25(OH)2D3.[123] Therefore, Vitamin D can regulate cytokine expression in diseased arteries [Figure 3]. Laboratory data suggest that 1,25(OH)2D3 influences cytokine production by both CD4 and CD8 subsets, preferentially inhibiting cytokine production (interleukin [IL]-2 and interferon-α) from Th1 cells and hence favoring Th2 responses with the production of IL-4, IL-5, and IL-10 as well as IL-6.[124],[125] It is these findings that might translate to a link between Vitamin D and AAA, a condition where Th2 responses predominate.[6],[126] Clinical studies of the effects of Vitamin D supplementation are limited.[6] In postmenopausal women, Vitamin D supplementation (2 g/day) increased CD3 and CD8 subsets of lymphocytes.[127] Therefore, Vitamin D may influence T-cell activity and inflammation of the artery wall through several different pathways. Wjst and Dold [128] hypothesized that deficiency of Vitamin D in early life leads to allergic diseases in later life. Allergy, autoimmune deficiency, and transplant rejection are all controlled by Th1 responses, inflammatory vascular disease being important in transplant rejection.[6] Although there is abundant experimental evidence (e.g., Räisänen-Sokolowski et al.[129]) to indicate that Vitamin D supplementation reduces transplant rejection, there are no clinical studies or trials of this phenomenon. Instead, Vitamin D supplementation is used to target posttransplantation osteoporosis.[6] Activated macrophages express 1α-hydroxylase and produce 1,25(OH)2D3.[130] This may have a role in limiting the extent of local inflammation [98],[131] but also has the potential to alter smooth muscle cell migration and proliferation in the vessel wall.
Figure 3: A schematic diagram describing the mechanism and application of vasculoprotective effect of Vitamin D

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Moreover, 1,25(OH)2D3 influences the function of macrophages, with subsequent effects on the production of alkaline phosphatase by cultured smooth muscle cells, promoting calcification.[105] These findings, together with the observation that Vitamin D supplementation increases serum transforming growth factor-type level,[132] provide other mechanistic possibilities for a more widespread influence of Vitamin D on peripheral arterial disease.[6]

  Role of Vitamin D in Atherosclerotic Arterial Disease Top

The harmful effect of excess Vitamin D on arteries has been studied in many animal models over the past 40 years or more.[133],[134] Numerous dosage regimens have been described although the majorities have used short courses of potentially toxic doses of Vitamin D resulting in acute hypercalcemia.[6] Chronic less toxic treatment also results in metastatic calcification and deteriorating renal function.[135] In general, Vitamin D results in arterial wall calcification and a variety of other “arteriosclerotic” changes.[6] Loss of collagen and disruption of elastic lamellae are additional features.[136],[137] These latter changes are usually associated with increased aortic stiffness [136] although one study reported a paradoxical reduction in stiffness.[138] Vitamin D also exacerbates the intimal hyperplasia seen in balloon-injured rat carotid arteries.[6],[139] This is probably caused by the stimulation of migration [16] and proliferation of smooth muscle cells.[112],[140],[141] Recently, the combination of Vitamin D2 and cholesterol has been used to induce both peripheral atherosclerosis and aortic valve stenosis in a rabbit model.[6],[137],[142] In this model, the addition of Vitamin D2 to the high cholesterol diet resulted in significantly higher levels of circulating cholesterol.[142] A combination of Vitamin D and nicotine, causing hypercalcemia, results in stiffer rat conductance arteries and exacerbates the atherosclerotic effects of cholesterol feeding.[136],[142] The relevance of any of these models to the development of cardiovascular disease in humans is uncertain.[6] Another possible link between Vitamin D and peripheral arterial disease has been found in a study of transgenic rats that constitutively express Vitamin D-24-hydroxylase [which catalyzes the conversion of 25(OH)D3-24, 25(OH)2D3].[143] These rats had low levels of plasma 24, 25(OH)2D3), and developed hyperlipidemia and aortic atherosclerosis.[137],[143] This is an example of the complexity of the relationship between differing Vitamin D metabolites and the arterial wall.[6]

  Clinical Application of Vasculoprotective Effect of Vitamin D Top

Clinical trials using Vitamin D as supplement produced inconsistent findings.[17],[18],[19],[144],[145],[146],[147],[148],[149],[150],[151] Several RCTs [18],[19],[148],[149],[150] have shown that Vitamin D supplementation improves endothelial function while others not.[144],[145],[146],[151] The discrepancies may be due to various Vitamin D dosages or dosing interval, study duration, outcome measures, sample size, and participant features.[152] A study by Harris et al. reported that supplementation with 60,000 IU/month of oral D3 for 16 weeks is effective in improving vascular endothelial function in African-American adults with significant improvements in flow-mediated vasodilatation (FMD) (1.8 ± 1.3%).[148] Another study in 42 participants with Vitamin D insufficiency and normalization of serum 25(OH)D was associated with increases in reactive hyperemia index (0.38 ± 0.14, P = 0.009) and a decrease in mean arterial pressure (4.6 ± 2.3 mmHg, P = 0.02) after 6 months of supplementation.[153] A 16-week RCT [149] indicated that Vitamin D supplementation (2000 IU/day) decreased arterial stiffness by the mean pulse wave velocity reduced from 5.41 m/s at baseline to 5.33 m/s (P = 0.031). In another RCT,[17] which was conducted among diabetic patients with baseline 25(OH)D insufficiency, a single dose of 100,000 IU Vitamin D2 significantly improved FMD of the brachial artery by 2.3% at 8 weeks. A 9-month RCT [19] among 123 patients with congestive heart failure also indicated that 50 μg Vitamin D3 plus 500 mg Ca per day notably improves cytokine profiles and decreases PTH level compared with calcium alone. In contrast, a 16-week RCT [151] of Vitamin D replacement among 61 diabetic patients, both low-and high-dose Vitamin D3 supplementation (100,000 and 200,000 IU), failed to modulate FMD, although an effect on BP was noted.[152] A 1-month pilot study [144] among 62 patients with peripheral arterial disease and a single large dosage of 100,000 IU oral Vitamin D2 indicated nil effect on endothelial function and arterial stiffness. The nonsignificant finding of the pilot trial might be due to the short duration or underpowered study participants. However, one RCT among 114 postmenopausal women with serum low Vitamin D status (25(OH)D > 10 and < 60 ng/mL) reported that 2500 IU Vitamin D3 daily for 4 months did not improve endothelial function, arterial stiffness, or inflammation.[146]

Multivariable models showed no significant interactions between treatment group and Vitamin D status (<30 ng/mL). A number of RCTs evaluated the impact of Vitamin D supplementation on BP; however, the results are inconclusive. In a double-blind, placebo-controlled study in 1987, Lind et al.[55] observed reductions in the blood pressure of 39 hypertensive patients with Vitamin D supplementation. This reduction was also highlighted in another study on older women supplemented with calcium and Vitamin D.[21] Another trial observed that administration of 1,25(OH)2D3 reduced blood pressure as well as plasma renin activity and angiotensin II levels.[154] On the other hand, Thierry-Palmer et al.[155] increased the supply of Vitamin D in the diet of salt-sensitive rats that were administered a high-salt diet and observed an increase in serum 25(OH)D, but their hypertension was not alleviated. These findings could suggest that there is a potential difference in the effects on the Vitamin D endocrine system between salt-induced hypertension and essential hypertension. One prospective study on humans described endothelial dysfunction and oxidative stress with 25(OH)D deficiency that was significantly improved with Vitamin D supplementation.[18]

  Conclusion Remarks Top

In addition to its role in calcium and phosphate homeostasis, Vitamin D is important in many physiological and pathological processes relevant to vascular problems. Vitamin D is essential for the development and maintenance of a healthy arterial tree. 1,25(OH)2D3 influences the migration, proliferation, gene expression of VSMCs, elastogenesis, and immunomodulation, all processes which are involved in the pathogenesis of atherosclerotic and aneurysmal arterial disease. 1,25(OH)2D3 has additional, poorly understood, nongenomic effects on vessel contractility in essential hypertension and is likely to have a pivotal role in the paradoxical association between osteoporosis and vascular calcification. Vitamin D may influence blood pressure by functioning as an endogenous inhibitor of the RAAS, interacting with salt and the RAAS to modulate vascular smooth muscle tone and indirectly affecting the vascular endothelium. In general, in animal experiments, implicated 1,25-dihydroxyvitamin D inhibits renin expression in the juxtaglomerular apparatus and blocks proliferation of VSMCs, which could influence systemic blood pressure [Figure 3].

Vitamin D has multiple immunomodulatory effects and regulates cytokines, profibrotic and proinflammatory pathways, and the renin–angiotensin system through VDR. Some effects, such as downregulation of TGF-1, may occur through Vitamin D-mediated nongenomic pathways.


First and foremost, I would like to thank God with the strength he allowed me from the beginning to the end. I would like to express my sincere gratitude to my colleague Professor Andualem Mossie for his excellent guidance, support, and encouragement throughout my research work.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]


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