The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
REVIEW ARTICLE

New Insights on Low Vitamin D Plasma Concentration as a Potential Cardiovascular Risk Factor.



Mattia Bellan1, 2, 3, *, Paolo Marzullo3, 4
1 Division of Internal Medicine, “Sant’Andrea Hospital”, Vercelli,Italy.
2 Department of Translational Medicine,Università del Piemonte Orientale UPO, Novara, Italy.
3 Interdisciplinary Research Center of Autoimmune Diseases, Novara, Italy.
4 Division of General Medicine, Ospedale S. Giuseppe, I.R.C.C.S. Istituto Auxologico Italiano, Verbania, Italy

Abstract

The role of Vitamin D hormone in human health and disease is still debated. Recently, growing attention has been paid to its putative role in cardiovascular system homeostasis with several studies that suggested a correlation between low vitamin D levels and increased cardiovascular risk. Several mechanisms are involved in the development of cardiovascular diseases: systemic inflammation, endothelial dysfunction, arterial hypertension and insulin resistance. In the present paper, we have revised the current literature supporting a role for vitamin D in the development of these pathogenetic processes. Finally, we have evaluated the current evidence linking vitamin D to atherosclerosis and its natural consequence, cardiovascular diseases.

Keywords: Vitamin D, Cardiovascular Risk, Cardiovascular Diseases, Insulin Resistance, Inflammation, Atherosclerosis.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
Issue: Suppl-1, M6
First Page: 261
Last Page: 278
Publisher Id: TORJ-12-261
DOI: 10.2174/1874312901812010261

Article History:

Received Date: 12/02/2018
Revision Received Date: 01/06/2018
Acceptance Date: 12/06/2018
Electronic publication date: 27/12/2018
Collection year: 2018

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© 2018 Bellan and Marzullo .

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address Correspondence to this author at the Department of Translational Medicine, Università del Piemonte Orientale UPO, via Solaroli 17, 28100 Novara, Italy. E-mail:mattia.bellan@med.uniupo.it




1. INTRODUCTION

Vitamin D is a fat-soluble hormone, the main activity of which is the regulation of calcium/phosphate metabolism. This bone-related activity is accomplished by acting with calcium-sparing effects on the gut [1Christakos S, Lieben L, Masuyama R, Carmeliet G. Vitamin D endocrine system and the intestine, Bonekey Rep 2014; 3: 496.[http://dx.doi.org/10.1038/bonekey.2013.230] [PMID: 24605213] ], the parathyroid glands [2Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1992; 89(17): 8097-101.[http://dx.doi.org/10.1073/pnas.89.17.8097] [PMID: 1325645] -4Canaff L, Hendy GN. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem 2002; 277(33): 30337-50.[http://dx.doi.org/10.1074/jbc.M201804200] [PMID: 12036954] ] and the kidney [5Jeon US. Kidney and calcium homeostasis Electrolyte Blood Press 2008; 6(2): 68-76.[http://dx.doi.org/10.5049/EBP.2008.6.2.68] [PMID: 24459525] ]. Vitamin D plays a crucial role for bone metabolism not only because calcium and phosphate are essential components of bone turnover mechanisms, but also because vitamin D can directly control the physiological turnover of bone at the level of osteoblasts and osteoclasts [6Noda M, Vogel RL, Craig AM, Prahl J, DeLuca HF, Denhardt DT. Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression. Proc Natl Acad Sci USA 1990; 87(24): 9995-9.[http://dx.doi.org/10.1073/pnas.87.24.9995] [PMID: 2175918] -9Khosla S. Minireview: The opg/rankl/rank system, Endocrinology 2001; 142(12): 5050-5.[http://dx.doi.org/10.1210/endo.142.12.8536] [PMID: 11713196] ]. There is overwhelming evidence, however, that Vitamin D Receptor (VDR) is expressed not only by cognate vitamin D targets but also by other cell types and tissues, implying that vitamin D has far a wider role in human physiology than previously thought. New putative functions of vitamin D have thus been explored and confirmed by both preclinical in-vitro and in-vivo studies. For instance, vitamin D is able to induce epidermal cells differentiation [10Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1 alpha,25-dihydroxyvitamin D3. Endocrinology 1983; 113(6): 1950-7.[http://dx.doi.org/10.1210/endo-113-6-1950] [PMID: 6196178] ], has a crucial role in proliferation and differentiation of the nervous system, affecting neuroprotection, neurotransmission, and neuroplasticity [11Di Somma C, Scarano E, Barrea L, et al. Vitamin D and neurological diseases: An endocrine view. Int J Mol Sci 2017; 18(11): E2482.[http://dx.doi.org/10.3390/ijms18112482] [PMID: 29160835] ]. Furthermore, vitamin D has antiproliferative actions [12Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: An endocrine society scientific statement. Endocr Rev 2012; 33(3): 456-92.[http://dx.doi.org/10.1210/er.2012-1000] [PMID: 22596255] ] and regulates both the innate and adaptive immune system activity [13Bikle DD. Vitamin D and the immune system: Role in protection against bacterial infection. Curr Opin Nephrol Hypertens 2008; 17(4): 348-52.[http://dx.doi.org/10.1097/MNH.0b013e3282ff64a3] [PMID: 18660668] -21Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol 1998; 160(11): 5314-9.[PMID: 9605130] ].

Potential new functions of vitamin D have been recently suggested for the regulation of cardiovascular health, leading to the hypothesis that low vitamin D levels can be considered as a new potential marker of cardiovascular risk [22Grübler MR, März W, Pilz S, et al. Vitamin-D concentrations, cardiovascular risk and events - A review of epidemiological evidence. Rev Endocr Metab Disord 2017; 18(2): 259-72.[http://dx.doi.org/10.1007/s11154-017-9417-0] [PMID: 28451877] ]. This inference takes origin from several associative observations, the most convincing of which are the wide expression of the VDR in the cardiovascular system [23Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest 1989; 83(6): 1903-15.[http://dx.doi.org/10.1172/JCI114097] [PMID: 2542376] ] and the inverse correlation existing between low vitamin D levels and important cardiovascular risk factors, such as systemic inflammation [24Liefaard MC, Ligthart S, Vitezova A, et al. Vitamin D and C-reactive protein: a mendelian randomization study. PLoS One 2015; 6: 10:e0131740.], arterial hypertension [25Feneis JF, Arora RR. Role of vitamin D in blood pressure homeostasis. Am J Ther 2010; 17(6): e221-9.[http://dx.doi.org/10.1097/MJT.0b013e3181d16999] [PMID: 20216204] ], insulin resistance [26Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: The Medical Research Council Ely Prospective Study 1990-2000. Diabetes 2008; 57(10): 2619-25.[http://dx.doi.org/10.2337/db08-0593] [PMID: 18591391] ], and endothelial dysfunction [27Oruc CU, Akpinar YE, Amikishiyev S, et al. Hypovitaminosis D is associated with endothelial dysfunction in patients with metabolic syndrome. Curr Vasc Pharmacol 2017; 15(2): 152-7.[http://dx.doi.org/10.2174/1570161114666161003093443] [PMID: 27697067] ].

In this paper, we aim to provide an overview of current evidence linking vitamin D to the cardiovascular risk, focusing our attention on the potential role of this hormone in the pathogenesis of atherosclerosis and Cardiovascular Diseases (CVDs).

1.1. Vitamin D Metabolism and Vitamin D Deficiency

Although several foods are dietary sources of vitamin D, endogenous synthesis accounts for the largest amount of active vitamin D in humans. In the skin, 7-dehydrocholesterol is photolysed in cholecalciferol (vitamin D3) after the exposure to UV rays [28Avioli LV. Absorption and metabolism of vitamin D3 in man. Am J Clin Nutr 1969; 22(4): 437-46.[http://dx.doi.org/10.1093/ajcn/22.4.437] [PMID: 4305087] ]. Cholecalciferol is then hydroxylated to 25-hydroxyvitamin D [25(OH)D3] in the liver [29Ohyama Y, Yamasaki T. Eight cytochrome P450s catalyze vitamin D metabolism. Front Biosci 2004; 9: 3007-18.[http://dx.doi.org/10.2741/1455] [PMID: 15353333] ]; 25(OH)D3, also known as calcifediol, circulates in the bloodstream bound to the vitamin D Binding Protein (DBP) and, minimally, as a free hormone. DBP, more generally, act as a carrier for all the isoforms of vitamin D [30DeLuca HF. 25-Hydroxycholecalciferol, the probable metabolically active form of vitamin D. Isolation, identification, and subcellular location. Am J Clin Nutr 1969; 22(4): 412-24.[http://dx.doi.org/10.1093/ajcn/22.4.412] [PMID: 4305084] , 31Daiger SP, Schanfield MS, Cavalli-Sforza LL. Group-specific component (Gc) proteins bind vitamin D and 25-hydroxyvitamin D. Proc Natl Acad Sci USA 1975; 72(6): 2076-80.[http://dx.doi.org/10.1073/pnas.72.6.2076] [PMID: 49052] ]. Vitamin D is finally activated into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (also termed calcitriol) by the 1α-hydroxylase (CYP27B1), in the kidney [32Norman AW. Evidence for a new kidney-produced hormone, 1,25-dihydroxycholecalciferol, the proposed biologically active form of vitamin D. Am J Clin Nutr 1971; 24(11): 1346-51.[http://dx.doi.org/10.1093/ajcn/24.11.1346] [PMID: 4330040] ]. The activity of the CYP27B1 is strictly controlled by parathyroid hormone (PTH), in a positive fashion [33Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 1972; 69(7): 1673-6.[http://dx.doi.org/10.1073/pnas.69.7.1673] [PMID: 4340153] ], and calcium and 1,25(OH)2D3, in a negative fashion [34Ghazarian JG, Jefcoate CR, Knutson JC, Orme-Johnson WH, DeLuca HF. Mitochondrial cytochrome p450. A component of chick kidney 25-hydrocholecalciferol-1alpha-hydroxylase. J Biol Chem 1974; 249(10): 3026-33.[PMID: 4151488] ]. The inactivation of 1,25(OH)2D3 is mediated by the CYP24A1 enzyme, which catalyzes the conversion to a 100-fold less active metabolite [35Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev 1998; 78(4): 1193-231.[http://dx.doi.org/10.1152/physrev.1998.78.4.1193] [PMID: 9790574] ].

1,25(OH)2D3 acts by binding the VDR, a nuclear receptor which heterodimerizes with the Retinoid X Receptor (RXR); the VDR/RXR complex moves from the cytoplasm to the nucleus and acts to upregulate or downregulate the expression of many target genes [36Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature 1992; 355(6359): 446-9.[http://dx.doi.org/10.1038/355446a0] [PMID: 1310351] ].

Vitamin D deficiency causes a decrease in intestinal dietary calcium and phosphorus absorption, leading to secondary hyperparathyroidism [37Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.[http://dx.doi.org/10.1056/NEJMra070553] [PMID: 17634462] , 38Heaney RP. Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr 2004; 80(6)(Suppl.): 1706S-9S.[http://dx.doi.org/10.1093/ajcn/80.6.1706S] [PMID: 15585791] ], which maintains serum calcium in the normal range at the expense of mobilizing calcium from the skeleton and increasing phosphorus wasting in the kidneys. This results in an inadequate calcium-phosphorus product and in a mineralization defect in the skeleton, leading to rickets in children [39Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006; 116(8): 2062-72.[http://dx.doi.org/10.1172/JCI29449] [PMID: 16886050] ] and osteomalacia in adults [40Annweiler C, Montero-Odasso M, Schott AM, Berrut G, Fantino B, Beauchet O. Fall prevention and vitamin D in the elderly: An overview of the key role of the non-bone effects. J Neuroeng Rehabil 2010; 7: 50.[http://dx.doi.org/10.1186/1743-0003-7-50] [PMID: 20937091] -42Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003; 78(12): 1463-70.[http://dx.doi.org/10.4065/78.12.1463] [PMID: 14661675] ].

Although 25(OH)D3 is not the most active metabolite, its stable concentrations and long half-life make it a reliable plasmatic marker of vitamin D status [43Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008; 87(4): 1087S-91S.[http://dx.doi.org/10.1093/ajcn/87.4.1087S] [PMID: 18400739] ]. The definition of vitamin D adequacy is historically based upon the identification of the plasma 25(OH)D3 threshold able to suppress PTH synthesis [44Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997; 7(5): 439-43.[http://dx.doi.org/10.1007/s001980050030] [PMID: 9425501] ]. Although no definitive consensus currently exists, the majority of authors would agree with the definition of vitamin D status as deficient for 25(OH)D3 concentration lower than 50 nmol/l (20 ng/ml), insufficient for 50-75 nmol/l (20-30 ng/ml) and adequate for 75-250 nmol/l (30-100 ng/ml) [45Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96(7): 1911-30.[http://dx.doi.org/10.1210/jc.2011-0385] [PMID: 21646368] ]. Hypovitaminosis D is a diffuse health issue worldwide, with a very high prevalence either in otherwise healthy or in hospitalized adults [46Mithal A, Wahl DA, Bonjour JP, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int 2009; 20(11): 1807-20.[http://dx.doi.org/10.1007/s00198-009-0954-6] [PMID: 19543765] -49Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006; 81(3): 353-73.[http://dx.doi.org/10.4065/81.3.353] [PMID: 16529140] ]. Its prevention and correction are therefore essential for bone health, but also necessary for its putative, collateral advantages on different aspects of human physiology. Oral cholecalciferol represents the gold standard for vitamin D supplementation, in healthy subjects with neither malabsorption nor chronic kidney disease; either daily supplementation or loading-dose based regimens have been proposed, although the best supplementation strategy is still to be defined [45Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96(7): 1911-30.[http://dx.doi.org/10.1210/jc.2011-0385] [PMID: 21646368] , 50Kuwabara A, Tsugawa N, Tanaka K, et al. Improvement of vitamin D status in japanese institutionalized elderly by supplementation with 800 IU of vitamin D(3). J Nutr Sci Vitaminol (Tokyo) 2009; 55(6): 453-8.[http://dx.doi.org/10.3177/jnsv.55.453] [PMID: 20086314] -55Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial. JAMA 2010; 303(18): 1815-22.[http://dx.doi.org/10.1001/jama.2010.594] [PMID: 20460620] ].

2. VITAMIN D AND SYSTEMIC INFLAMMATION

One of the best characterized extra-skeletal activities of vitamin D is the regulation of the immune system and inflammatory response.

In vitro, 1,25(OH)2D3 affects functional activities of monocytes and macrophages. Tumor cell cytotoxicity, phagocytosis, and mycobactericidal activity of monocytes/macrophages are enhanced by exposure to active vitamin D [56Walters MR. Newly identified actions of the vitamin D endocrine system. Endocr Rev 1992; 13(4): 719-64.[PMID: 1333949] , 57Bikle DD. Vitamin D and the immune system: Role in protection against bacterial infection. Curr Opin Nephrol Hypertens 2008; 17(4): 348-52.[http://dx.doi.org/10.1097/MNH.0b013e3282ff64a3] [PMID: 18660668] ], while monocyte function as an Antigen Presenting Cell (APC) is decreased [58Xu H, Soruri A, Gieseler RKH, Peters JH. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 1993; 38(6): 535-40.[http://dx.doi.org/10.1111/j.1365-3083.1993.tb03237.x] [PMID: 8256111] ], as well as the production of proinflammatory cytokines such as Interleukin 6 (IL-6) and Tumor Necrosis Factor α (TNFα) [59Zhang Y, Leung DY, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 2012; 188(5): 2127-35.[http://dx.doi.org/10.4049/jimmunol.1102412] [PMID: 22301548] ]. Furthermore, 1,25(OH)2D3 promotes terminal differentiation of monocytes towards a macrophage phenotype [60Kreutz M, Andreesen R. Induction of human monocyte to macrophage maturation in vitro by 1,25-dihydroxyvitamin D3. Blood 1990; 76(12): 2457-61.[PMID: 2265241] ] and inhibits the differentiation of murine and human Monocytes into Dendritic Cells (DCs) in vitro [61Piemonti L, Monti P, Sironi M, et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 2000; 164(9): 4443-51.[http://dx.doi.org/10.4049/jimmunol.164.9.4443] [PMID: 10779743] ]. 1,25(OH)2D3 also impairs DCs function as APCs, by downregulating MHC II and costimulatory molecules expression [62Griffin MD, Lutz WH, Phan VA, Bachman LA, McKean DJ, Kumar R. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun 2000; 270(3): 701-8.[http://dx.doi.org/10.1006/bbrc.2000.2490] [PMID: 10772887] ], as well as chemotaxis [63Gauzzi MC, Purificato C, Donato K, et al. Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: Impairment of functional activities and chemotaxis. J Immunol 2005; 174(1): 270-6.[http://dx.doi.org/10.4049/jimmunol.174.1.270] [PMID: 15611249] ], thus affecting adaptive immune system, which is strictly regulated by DCs activity. However, vitamin D also directly regulates adaptive immunity. In fact, it is able to inhibit the proliferation and to induce the apoptosis of activated B cells; furthermore, 1,25(OH)2D3 inhibits plasma cells and post-switch memory B cells differentiation and significantly reduces immunoglobulin secretion [64Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179(3): 1634-47.[http://dx.doi.org/10.4049/jimmunol.179.3.1634] [PMID: 17641030] ]. Finally, 1,25(OH)2D3 acts on T cells: vitamin D inhibits T cells cytotoxic activity by suppressing Fas-ligand expression in activated T cells [65Cippitelli M, Fionda C, Di Bona D, et al. Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes. J Immunol 2002; 168(3): 1154-66.[http://dx.doi.org/10.4049/jimmunol.168.3.1154] [PMID: 11801650] ] and drives CD4+ differentiation, leading to a suppression of Th1 and Th17 function towards a more favourable and less inflammatory Th2 or Treg phenotype. As such, 1,25(OH)2D3 reduces the expression of the Th1 associated cytokines IL-2, TNF-α, and IFNγ [66Rigby WF, Denome S, Fanger MW. Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. J Clin Invest 1987; 79(6): 1659-64.[http://dx.doi.org/10.1172/JCI113004] [PMID: 2884234] ]. On the other hand, key Th2 cytokines like IL-4 and IL-5 are upregulated [67Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol 1998; 160(11): 5314-9.[PMID: 9605130] , 68Sloka S, Silva C, Wang J, Yong VW. Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. J Neuroinflammation 2011; 8: 56.[http://dx.doi.org/10.1186/1742-2094-8-56] [PMID: 21605467] ]. Th17 is a specific subset of CD4+ cells able to produce IL-17A, IL-17F, IL-21, IL-22 [69Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic potential of targeting the th17/treg axis in autoimmune disorders. Molecules 2017; 22(1): E134.[http://dx.doi.org/10.3390/molecules22010134] [PMID: 28098832] ], thus playing a pivotal role in inflammation. On the contrary, regulatory/suppressive T cells (Treg) contribute to the maintenance of self-tolerance. Treg cells account for 5-10% of total number of T CD4+ cells in healthy humans and play an important role in supporting immune homeostasis by producing anti-inflammatory cytokines, including IL-10 and TGF-β1 [70Loser K, Beissert S. Regulatory T cells: Banned cells for decades. J Invest Dermatol 2012; 132(3 Pt 2): 864-71.[http://dx.doi.org/10.1038/jid.2011.375] [PMID: 22158548] -72Schon HT, Weiskirchen R. Immunomodulatory effects of transforming growth factor-β in the liver. Hepatobiliary Surg Nutr 2014; 3(6): 386-406.[PMID: 25568862] ]. 1,25(OH)2D3 has been shown able to induce the differentiation of Treg by enhancing the expression of CTLA-4 and Foxp3, while inhibiting IL-17, IL-21 and IFNγ expression [73Jeffery LE, Wood AM, Qureshi OS, et al. Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. J Immunol 2012; 189(11): 5155-64.[http://dx.doi.org/10.4049/jimmunol.1200786] [PMID: 23087405] ]. On the contrary, 1,25(OH)2D3 inhibits Th17 proliferation [74Zhang H, Shih DQ, Zhang X. Mechanisms underlying effects of 1,25-Dihydroxyvitamin D3 on the Th17 cells. Eur J Microbiol Immunol (Bp) 2013; 3(4): 237-40.[http://dx.doi.org/10.1556/EuJMI.3.2013.4.1] [PMID: 24294492] ]. As a result, the secretion of TGF-β1 is enhanced [75Zhou Q, Qin S, Zhang J, Zhon L, Pen Z, Xing T. 1,25(OH)2D3 induces regulatory T cell differentiation by influencing the VDR/PLC-γ1/TGF-β1/pathway. Mol Immunol 2017; 91: 156-64.[http://dx.doi.org/10.1016/j.molimm.2017.09.006] [PMID: 28926770] ], paralleling a decrease in Th17 cytokines signature production [76Joshi S, Pantalena LC, Liu XK, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011; 31(17): 3653-69.[http://dx.doi.org/10.1128/MCB.05020-11] [PMID: 21746882] ].

In vitro data led many groups to investigate whether plasma 25(OH)D3 concentration could independently predict the risk for autoimmune diseases and whether vitamin D supplementation could benefit the treatment of inflammatory/immune conditions [77Sainaghi PP, Bellan M, Carda S, et al. Hypovitaminosis D and response to cholecalciferol supplementation in patients with autoimmune and non-autoimmune rheumatic diseases. Rheumatol Int 2012; 32(11): 3365-72.[http://dx.doi.org/10.1007/s00296-011-2170-x] [PMID: 22045518] -85Chandrashekara S, Patted A. Role of vitamin D supplementation in improving disease activity in rheumatoid arthritis: An exploratory study. Int J Rheum Dis 2017; 20(7): 825-31.[http://dx.doi.org/10.1111/1756-185X.12770] [PMID: 26481198] ]. However, there is still a relevant gap between the strength of the in vitro data and the faintness of the in vivo findings, which do not allow, at the moment, to clarify the real relevance of vitamin D in the development of autoimmunity.

2.1. Vitamin D and Endothelial Dysfunction

Vitamin D activity has also been related to the vascular system. In fact, endothelial cells express both the VDR and the CYP27B1 enzyme, thus allowing the autocrine activation of 25(OH)D3 [86Zehnder D, Bland R, Chana RS, et al. Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: A novel autocrine determinant of vascular cell adhesion. J Am Soc Nephrol 2002; 13(3): 621-9.[PMID: 11856765] , 87Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest 1989; 83(6): 1903-15.[http://dx.doi.org/10.1172/JCI114097] [PMID: 2542376] ]. This is particularly relevant, since vitamin D has a potential protective effect on the vascular endothelium. In vitro, vitamin D is able to induce the synthesis of Nitric Oxide (NO) through regulation of the endothelial isoform of NO synthase (eNOS) [88Molinari C, Uberti F, Grossini E, et al. 1α,25-dihydroxycholecalciferol induces nitric oxide production in cultured endothelial cells. Cell Physiol Biochem 2011; 27(6): 661-8.[http://dx.doi.org/10.1159/000330075] [PMID: 21691084] ]. Experimentally, administration of 1,25(OH)2D3 reduces inflammatory and atherosclerotic parameters [89Tahawi Z, Orolinova N, Joshua IG, Bader M, Fletcher EC. Altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. J Appl Physiol 2001; 90(5): 2007-13.[http://dx.doi.org/10.1152/jappl.2001.90.5.2007] [PMID: 11299297] ] and blunts the deleterious effect of advanced glycation end products on the endothelium, thereby improving the activity of the NO system [90Talmor Y, Golan E, Benchetrit S, et al. Calcitriol blunts the deleterious impact of advanced glycation end products on endothelial cells. Am J Physiol Renal Physiol 2008; 294(5): F1059-64.[http://dx.doi.org/10.1152/ajprenal.00051.2008] [PMID: 18353875] ]. Furthermore, 1,25(OH)2D3 stimulates the migration and proliferation of endothelial cells [91Molinari C, Rizzi M, Squarzanti DF, Pittarella P, Vacca G, Renò F. 1α,25-Dihydroxycholecalciferol (Vitamin D3) induces no-dependent endothelial cell proliferation and migration in a three-dimensional matrix. Cell Physiol Biochem 2013; 31(6): 815-22.[http://dx.doi.org/10.1159/000350099] [PMID: 23816836] ] and in vitro vitamin D treatment improves the capacity of endothelial progenitor cells, isolated from diabetic subjects, to form colonies [92Hammer Y, Soudry A, Levi A, et al. Effect of vitamin D on endothelial progenitor cells function. PLoS One 2017; 12(5): e0178057.[http://dx.doi.org/10.1371/journal.pone.0178057] [PMID: 28545072] ]; taken together, these findings suggest a potential role for this hormone in vessel damage healing. In addition to its ability to modulate the effects of proinflammatory cytokines on the vascular endothelium [93Suzuki Y, Ichiyama T, Ohsaki A, Hasegawa S, Shiraishi M, Furukawa S. Anti-inflammatory effect of 1alpha,25-dihydroxyvitamin D(3) in human coronary arterial endothelial cells: Implication for the treatment of Kawasaki disease. J Steroid Biochem Mol Biol 2009; 113(1-2): 134-8.[http://dx.doi.org/10.1016/j.jsbmb.2008.12.004] [PMID: 19138739] ] and to decrease the expression of endothelial adhesion molecules [94Kanikarla-Marie P, Jain SK. 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). J Steroid Biochem Mol Biol 2016; 159: 94-101.[http://dx.doi.org/10.1016/j.jsbmb.2016.03.002] [PMID: 26949104] , 95Kudo K, Hasegawa S, Suzuki Y, et al. 1α,25-Dihydroxyvitamin D(3) inhibits vascular cellular adhesion molecule-1 expression and interleukin-8 production in human coronary arterial endothelial cells. J Steroid Biochem Mol Biol 2012; 132(3-5): 290-4.[http://dx.doi.org/10.1016/j.jsbmb.2012.07.003] [PMID: 22841897] ], vitamin D can also exert antioxidant properties [96Uberti F, Lattuada D, Morsanuto V, et al. Vitamin D protects human endothelial cells from oxidative stress through the autophagic and survival pathways. J Clin Endocrinol Metab 2014; 99(4): 1367-74.[http://dx.doi.org/10.1210/jc.2013-2103] [PMID: 24285680] ].

In vivo, 25(OH)D3 concentrations are related to endothelial dysfunction. In fact, vitamin D status has been inversely associated with the concentration of circulating markers of endothelial dysfunction in obese patients [97Ilinčić B, Stokić E, Stošić Z, et al. Vitamin D status and circulating biomarkers of endothelial dysfunction and inflammation in non-diabetic obese individuals: A pilot study. Arch Med Sci 2017; 13(1): 53-60.[http://dx.doi.org/10.5114/aoms.2016.61812] [PMID: 28144255] ]. Consistently, hypovitaminosis D has been associated to endothelial dysfunction in patients affected by metabolic syndrome, chronic kidney disease and rheumatoid arthritis [98Oruc CU, Akpinar YE, Amikishiyev S, et al. Hypovitaminosis D is associated with endothelial dysfunction in patients with metabolic syndrome. Curr Vasc Pharmacol 2017; 15(2): 152-7.[http://dx.doi.org/10.2174/1570161114666161003093443] [PMID: 27697067] -100Zhang QY, Jiang CM, Sun C, et al. Hypovitaminosis D is associated with endothelial dysfunction in patients with non-dialysis chronic kidney disease. J Nephrol 2015; 28(4): 471-6.[http://dx.doi.org/10.1007/s40620-014-0167-8] [PMID: 25515034] ]. In healthy subjects, a 25(OH)D3 <25 mmol/l (10 ng/ml) is associated with a significantly lower brachial artery flow-mediated dilatation (FMD), an important marker of endothelial dysfunction, with respect to subjects with a normal vitamin D status. Interestingly, a high-dose supplementation regimen has been reported to lead to a significant improvement of FMD [101Tarcin O, Yavuz DG, Ozben B, et al. Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. J Clin Endocrinol Metab 2009; 94(10): 4023-30.[http://dx.doi.org/10.1210/jc.2008-1212] [PMID: 19584181] ]. Following this finding, the effect of a vitamin D supplementation regimen on endothelial dysfunction has been investigated in different trials, leading to conflicting results. While cholecalciferol supplementation significantly increased the FMD in a trial conducted on patients affected by essential arterial hypertension and hypovitaminosis D [102Carrara D, Bruno RM, Bacca A, et al. Cholecalciferol treatment downregulates renin-angiotensin system and improves endothelial function in essential hypertensive patients with hypovitaminosid D. J Hypertens 2016; 34(11): 2199-205.[http://dx.doi.org/10.1097/HJH.0000000000001072] [PMID: 27648718] ], other studies presented different results. However, the discrepancies observed could depend on differences in the studied cohorts, supplementation regimens and endpoints used to define the outcome. In a trial recently published by Borgi et al. [103Borgi L, McMullan C, Wohlhueter A, Curhan GC, Fisher ND, Forman JP. Effect of vitamin D on endothelial function: A randomized, double-blind, placebo-controlled trial. Am J Hypertens 2017; 30(2): 124-9.[http://dx.doi.org/10.1093/ajh/hpw135] [PMID: 28077419] ], the outcomes and the supplementation regimen were similar to those of the study by Carrara et al. [102Carrara D, Bruno RM, Bacca A, et al. Cholecalciferol treatment downregulates renin-angiotensin system and improves endothelial function in essential hypertensive patients with hypovitaminosid D. J Hypertens 2016; 34(11): 2199-205.[http://dx.doi.org/10.1097/HJH.0000000000001072] [PMID: 27648718] ]. Borgi did not find any effect of vitamin D supplementation on endothelial function. However, the populations studied were very different, being in this last trial included overweight and obese subjects who are known to have an impaired bioavailability of vitamin D [104Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72(3): 690-3.[http://dx.doi.org/10.1093/ajcn/72.3.690] [PMID: 10966885] ], which could have biased the negative results. On the contrary, in a trial by Dalan et al. conducted on diabetic subjects, different endpoints were used and cholecalciferol supplementation was based on a lower dose regimen, which could justify the difference observed [105Dalan R, Liew H, Assam PN, et al. A randomised controlled trial evaluating the impact of targeted vitamin D supplementation on endothelial function in type 2 diabetes mellitus: The dimension trial. Diab Vasc Dis Res 2016; 13(3): 192-200.[http://dx.doi.org/10.1177/1479164115621667] [PMID: 26818228] ]. Therefore, these trials cannot be compared and further studies are required to better clarify the impact of vitamin D supplementation on endothelial function.

2.2. Vitamin D and Arterial Hypertension

High blood pressure is a recognized risk factor for disease and premature death [106Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: A systematic analysis for the global burden of disease study 2010. Lancet 2012; 380(9859): 2224-60.[http://dx.doi.org/10.1016/S0140-6736(12)61766-8] [PMID: 23245609] ]. Blood pressure is regulated by different mechanisms that include sodium and fluid balance as well as vasomotor tone. Both mechanisms are affected by genetic and environmental factors, and are controlled by hormonal, nervous, paracrine, neuroendocrine and intracellular feedback loops [107Staessen JA, Wang J, Bianchi G, Birkenhäger WH. Essential hypertension. Lancet 2003; 361(9369): 1629-41.[http://dx.doi.org/10.1016/S0140-6736(03)13302-8] [PMID: 12747893] ]. In vitro and in vivo data have suggested that vitamin D could be implicated in the control of blood pressure through inter-related factors, such as the Renin-Angiotensin-Aldosterone System (RAAS), sympathetic activation and genetics. Vitamin D has been shown to exert inhibitory effects on the RAAS through modulation of the renin gene via VDR-dependent mechanism [108Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J. Vitamin D: A negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 2004; 89-90(1-5): 387-92.[http://dx.doi.org/10.1016/j.jsbmb.2004.03.004] [PMID: 15225806] ]. Mice lacking the VDR were prone to develop excess plasma renin activity and hypertension [109Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002; 110(2): 229-38.[http://dx.doi.org/10.1172/JCI0215219] [PMID: 12122115] ], as well as increased susceptibility to obstructive renal injury [110Zhang Y, Kong J, Deb DK, Chang A, Li YC. Vitamin D receptor attenuates renal fibrosis by suppressing the renin-angiotensin system. J Am Soc Nephrol 2010; 21(6): 966-73.[http://dx.doi.org/10.1681/ASN.2009080872] [PMID: 20378820] ]. All these effects could be prevented by treatment with ACE inhibitor or AT1 receptor antagonism. Similar negative consequences were observed in mice silenced for the CYP27B1 gene, while 1,25(OH)2D3 administration favored the regression of hypertension due to excess plasma renin activity, independent of calcium levels [111Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int 2008; 74(2): 170-9.[http://dx.doi.org/10.1038/ki.2008.101] [PMID: 18385669] , 112Sundersingh F, Plum LA, DeLuca HF. Vitamin D deficiency independent of hypocalcemia elevates blood pressure in rats. Biochem Biophys Res Commun 2015; 461(4): 589-91.[http://dx.doi.org/10.1016/j.bbrc.2015.04.069] [PMID: 25911319] ]. However, others observed that 1,25(OH)2D3 administration induced an increase in plasma renin activity [113Atchison DK, Harding P, Beierwaltes WH. Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and β-adrenergic activity. Am J Physiol Renal Physiol 2013; 305(8): F1109-17.[http://dx.doi.org/10.1152/ajprenal.00010.2013] [PMID: 23926179] ]. Interestingly, 4-week cholecalciferol administration to normal rats, at doses ranging from deficiency to toxic levels, generated a U-shaped dose-response curve on indices of arterial stiffness and systolic hypertension, implying that the vasoactive effects related to vitamin D likely reflect a balanced vitamin D status [114Mirhosseini NZ, Knaus SJ, Bohaychuk K, Singh J, Vatanparast HA, Weber LP. Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model. Br J Nutr 2016; 116(11): 1889-900.[http://dx.doi.org/10.1017/S0007114516004098] [PMID: 27964766] ]. Studies in non-hypertensive individuals maintained on dietary sodium balance showed that 25(OH)D3 deficiency was associated with increased renal vascular RAAS activity as well as increased angiotensin II levels [115Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension 2010; 55(5): 1283-8.[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.148619] [PMID: 20351344] ]. Nevertheless, the effect of vitamin D on renin–angiotensin system activation and blood pressure has been analyzed in a randomized control trial, and results showed no benefit from correcting vitamin D deficiency on RAAS activity or blood pressure after 8 weeks [116McMullan CJ, Borgi L, Curhan GC, Fisher N, Forman JP. The effect of vitamin D on renin-angiotensin system activation and blood pressure: A randomized control trial. J Hypertens 2017; 35(4): 822-9.[http://dx.doi.org/10.1097/HJH.0000000000001220] [PMID: 28033130] ].

Potential RAAS-independent mechanisms have also been claimed to explain the vitamin D-related effects on hypertension. Studies in rat showed that vitamin D deficiency results in increased cardiac contractility, hypertrophy and fibrosis and has profound effects on heart proteomics, structure and function [117Simpson RU. Evidence for a specific 1,25-dihydroxyvitamin D3 receptor in rat heart. Circulation 1983; 68: 239.]. The mechanism involves an increased expression of L-type calcium channels and sarcoplasmic reticulum calcium uptake [118Weishaar RE, Simpson RU. The involvement of the endocrine system in regulating cardiovascular function: Emphasis on vitamin D3. Endocr Rev 1989; 10(3): 351-65.[http://dx.doi.org/10.1210/edrv-10-3-351] [PMID: 2550215] ]. Ablation of the VDR in mice caused profound cardiac hypertrophy in the absence of significant modifications of the RAAS [119Simpson RU, Hershey SH, Nibbelink KA. Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. J Steroid Biochem Mol Biol 2007; 103(3-5): 521-4.[http://dx.doi.org/10.1016/j.jsbmb.2006.12.098] [PMID: 17275289] ]. Moreover, it was shown that vitamin D deficiency in growing rats promoted vascular oxidative stress and induced changes in cardiac expression of 51 genes, including genes involved in the regulation of oxidative stress and myocardial hypertrophy [120Argacha JF, Egrise D, Pochet S, et al. Vitamin D deficiency-induced hypertension is associated with vascular oxidative stress and altered heart gene expression. J Cardiovasc Pharmacol 2011; 58(1): 65-71.[http://dx.doi.org/10.1097/FJC.0b013e31821c832f] [PMID: 21499117] ]. Based on these results, anti-inflammatory activity of vitamin D could involve vascular endothelium and smooth muscle as a potential target of action. There is also evidence that vitamin D plays a role in sympathetic activation. Vitamin D deficiency in otherwise healthy subjects is associated with increased levels of plasma metanephrine, a marker of adrenal medulla activity [121Burt MG, Mangelsdorf BL, Stranks SN, Mangoni AA. Relationship between vitamin D status and autonomic nervous system activity. Nutrients 2016; 8(9): E565.[http://dx.doi.org/10.3390/nu8090565] [PMID: 27649235] ], while a study discriminating on the sympathetic effects of 25(OH)D3 and 1,25(OH)2D3 suggested that 1,25(OH)2D3 but not 25(OH)D3 deficiency are associated with dynamic autonomic dysfunction [122Mann MC, Exner DV, Hemmelgarn BR, et al. Vitamin D levels are associated with cardiac autonomic activity in healthy humans. Nutrients 2013; 5(6): 2114-27.[http://dx.doi.org/10.3390/nu5062114] [PMID: 23752493] ]. Furthermore, many studies pinpointed the vasoactive properties of vitamin D through modification of calcium homeostasis in vascular smooth muscle cells [123Vaidya A, Forman JP. Vitamin D and hypertension: Current evidence and future directions. Hypertension 2010; 56(5): 774-9.[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.140160] [PMID: 20937970] ].

As VDR is present in aortic endothelial, cardiomyocytes and vascular smooth muscle cells [124Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest 1989; 83(6): 1903-15.[http://dx.doi.org/10.1172/JCI114097] [PMID: 2542376] ] VDR polymorphisms and mutations affecting vitamin D synthesis/metabolism could play a role on the susceptibility to develop hypertension. BsmI polymorphism of the VDR gene was found to influence blood pressure in healthy men, while a positive relationship was noted between 25(OH)D3 levels and blood pressure only in men and not women with the BB genotype [125Muray S, Parisi E, Cardús A, Craver L, Fernández E. Influence of vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D on blood pressure in apparently healthy subjects. J Hypertens 2003; 21(11): 2069-75.[http://dx.doi.org/10.1097/00004872-200311000-00016] [PMID: 14597850] ]. A study on an Indian cohort also found important associations between hypertension and Fok I VDR polymorphism [rs2228570], which generates long and short variants of the VDR, independent of sex, family history and smoking [126Swapna N, Vamsi UM, Usha G, Padma T. Risk conferred by FokI polymorphism of Vitamin D Receptor (VDR) gene for essential hypertension. Indian J Hum Genet 2011; 17(3): 201-6.[http://dx.doi.org/10.4103/0971-6866.92104] [PMID: 22345993] , 127Kunutsor SK, Burgess S, Munroe PB, Khan H. Vitamin D and high blood pressure: Causal association or epiphenomenon? Eur J Epidemiol 2014; 29(1): 1-14.[http://dx.doi.org/10.1007/s10654-013-9874-z] [PMID: 24374742] ]. However, allelic frequencies and genotype distribution of FokI and BsmI VDR polymorphisms were not found associated with hypertensive status or renin activity in a small study on Italian individuals with essential hypertension [128Cottone S, Guarino L, Arsena R, et al. Vitamin D receptor gene polymorphisms and plasma renin activity in essential hypertensive individuals. J Hum Hypertens 2015; 29(8): 483-7.[http://dx.doi.org/10.1038/jhh.2014.113] [PMID: 25500899] ]. A recent meta-analysis reported that polymorphism in the 24-hydroxylase (CYP24A1) gene, which controls vitamin D metabolism, were the most significantly associated with systolic and diastolic blood pressure [129Wang L, Ma J, Manson JE, Buring JE, Gaziano JM, Sesso HD. A prospective study of plasma vitamin D metabolites, vitamin D receptor gene polymorphisms, and risk of hypertension in men. Eur J Nutr 2013; 52(7): 1771-9.[http://dx.doi.org/10.1007/s00394-012-0480-8] [PMID: 23262750] ]. Nevertheless, results from the Women’s Genome Health Study on 23,294 women and the International Consortium of Blood Pressure on 69,395 men and women of European ancestry only found associations with genes related with vitamin D metabolism and signaling which, however, disappeared after multiple testing corrections [130Wang L, Chu A, Buring JE, Ridker PM, Chasman DI, Sesso HD. Common genetic variations in the vitamin D pathway in relation to blood pressure. Am J Hypertens 2014; 27(11): 1387-95.[http://dx.doi.org/10.1093/ajh/hpu049] [PMID: 24688000] ]. In a Mendelian randomization study on 146,581 individuals, a link was suggested between low vitamin D and increased risk of hypertension using gene variants relating to 25(OH)D3 synthesis and metabolism, i.e. DHCR7 rs12785878, CYP2R1 rs12794714, GC rs2282679, and CYP24A1 rs6013897 [131Vimaleswaran KS, Cavadino A, Berry DJ, et al. Association of vitamin D status with arterial blood pressure and hypertension risk: A mendelian randomisation study. Lancet Diabetes Endocrinol 2014; 2(9): 719-29.[http://dx.doi.org/10.1016/S2213-8587(14)70113-5] [PMID: 24974252] ]. According to results, each 10% increase in genetically determined 25(OH)D3 levels was associated with a significant 0.29 mmHg decrease in diastolic blood pressure and 0.37 mmHg decrease in systolic blood pressure, conferring overall a 8.1% reduced risk of hypertension. This finding suggests that genetically affected risk factors related to the VDR are causally related to clinical outcomes [132Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ 2014; 349: g6330.[http://dx.doi.org/10.1136/bmj.g6330] [PMID: 25406188] ]. On the other hand, there is no evidence of a convincing relation between DBP and hypertension except for a Mendelian randomization study based on results from the Canadian Multicentre Osteoporosis Study, which however failed to document any association between DBP polymorphism rs2282679 and arterial blood pressure [133Leong A, Rehman W, Dastani Z, et al. The causal effect of vitamin D Binding Protein (DBP) levels on calcemic and cardiometabolic diseases: A mendelian randomization study. PLoS Med 2014; 11(10): e1001751.[http://dx.doi.org/10.1371/journal.pmed.1001751] [PMID: 25350643] ].

Studies on oral supplementation with vitamin D is found to lower blood pressure in hypertensive rats [134Borges AC, Feres T, Vianna LM, Paiva TB. Recovery of impaired K+ channels in mesenteric arteries from spontaneously hypertensive rats by prolonged treatment with cholecalciferol. Br J Pharmacol 1999; 127(3): 772-8.[http://dx.doi.org/10.1038/sj.bjp.0702581] [PMID: 10401569] , 135Feres T, Vianna LM, Paiva AC, Paiva TB. Effect of treatment with vitamin D3 on the responses of the duodenum of spontaneously hypertensive rats to bradykinin and to potassium. Br J Pharmacol 1992; 105(4): 881-4.[http://dx.doi.org/10.1111/j.1476-5381.1992.tb09072.x] [PMID: 1324053] ]. In humans, cross-sectional data suggest an association between low vitamin D intake (<400 IU per day) and an increase in blood pressure [136Sowers MR, Wallace RB, Lemke JH. The association of intakes of vitamin D and calcium with blood pressure among women. Am J Clin Nutr 1985; 42(1): 135-42.[http://dx.doi.org/10.1093/ajcn/42.1.135] [PMID: 3874536] ], and one study in black participants reported dose-dependent reductions in systolic blood pressure after 3 months of supplementation with 1000 IU, 2000 IU, and 4000 IU of vitamin D per day, i.e. 0.66, 3.4, and 4.0 mm Hg, respectively [137Forman JP, Scott JB, Ng K, et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 2013; 61(4): 779-85.[http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00659] [PMID: 23487599] ]. However, evidence from randomized controlled trials has not provided consistent evidence of a benefit. In an interventional study on vitamin D deficient elderly women, a combination of calcium and vitamin D supplementation was found to have a greater lowering effect on blood pressure than calcium alone [138Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab 2001; 86(4): 1633-7.[PMID: 11297596] ]. Another study on cholecalciferol supplementation by a dose that effectively increased vitamin D levels during winter months, showed no effects on 24-h blood pressure, yet a post-hoc subgroup analysis of 92 subjects with baseline 25(OH)D3 levels <32 ng/ml showed significant decreases in 24-h systolic and diastolic blood pressure [139Larsen T, Mose FH, Bech JN, Hansen AB, Pedersen EB. Effect of cholecalciferol supplementation during winter months in patients with hypertension: A randomized, placebo-controlled trial. Am J Hypertens 2012; 25(11): 1215-22.[http://dx.doi.org/10.1038/ajh.2012.111] [PMID: 22854639] ]. Oppositely, a trial on participants with arterial hypertension and 25(OH)D3 levels below 30 ng/mL failed to show significant effects of cholecalciferol supplementation on 24-hour systolic ambulatory blood pressure and several cardiovascular risk factors, while it pinpointed a significant increase in triglycerides [140Pilz S, Gaksch M, Kienreich K, et al. Effects of vitamin D on blood pressure and cardiovascular risk factors: A randomized controlled trial. Hypertension 2015; 65(6): 1195-201.[http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05319] [PMID: 25801871] ]. Similarly, other studies found that vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency [141Arora P, Song Y, Dusek J, et al. Vitamin D therapy in individuals with prehypertension or hypertension: The daylight trial. Circulation 2015; 131(3): 254-62.[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.011732] [PMID: 25359163] ].

Weaknesses inherent in observational studies, such as reverse causation, are a possible source for discrepancies between these studies, as well as differences in the therapeutic regimens and duration of vitamin D supplementation, or in baseline differences in 25(OH)D3 concentrations, blood pressure or obesity. Moreover, people with hypertension might move less outdoors or have poorer health than those moving actively. While current evidence remains elusive, it remains to be demonstrated that larger randomized controlled studies could really add more evidence of the benefits of vitamin D in cardiovascular health.

2.3. Vitamin D and Insulin Sensitivity

Many studies have provided in vitro and in vivo evidence that vitamin D has an effect on glucose metabolism, and hypovitaminosis D seems to detrimentally impact on insulin sensitivity both directly and indirectly via negative effects sorted by secondary hyperparathyroidism [142Alvarez JA, Ashraf AP, Hunter GR, Gower BA. Serum 25-hydroxyvitamin D and parathyroid hormone are independent determinants of whole-body insulin sensitivity in women and may contribute to lower insulin sensitivity in african americans. Am J Clin Nutr 2010; 92(6): 1344-9.[http://dx.doi.org/10.3945/ajcn.110.000976] [PMID: 20861177] ].

This association has been hypothesized on the basis of observational in vivo data. In a cross-sectional study on 3577 US adolescents, lower vitamin D concentrations were independently associated with Fasting Plasma Glucose (FPG), with the risk of Impaired Fasting Glucose (IFG) being doubled in patients at the lowest, compared to those at the highest quartile of vitamin D [143Reis JP, von Mühlen D, Miller ER III, Michos ED, Appel LJ. Vitamin D status and cardiometabolic risk factors in the united states adolescent population. Pediatrics 2009; 124(3): e371-9.[http://dx.doi.org/10.1542/peds.2009-0213] [PMID: 19661053] ]. Similar results have been obtained on a large cohort of adults, in a recent study which proved an inverse association between 25(OH)D3 plasma levels and FPG [144Pannu PK, Piers LS, Soares MJ, Zhao Y, Ansari Z. Vitamin D status is inversely associated with markers of risk for type 2 diabetes: A population based study in victoria, australia. PLoS One 2017; 12(6): e0178825.[http://dx.doi.org/10.1371/journal.pone.0178825] [PMID: 28575036] ]. Moreover, vitamin D status was inversely associated to HbA1C, as previously reported in other cross-sectional studies [145Kositsawat J, Kuchel GA, Tooze JA, et al. Vitamin D insufficiency and abnormal hemoglobin a1c in black and white older persons. J Gerontol A Biol Sci Med Sci 2015; 70(4): 525-31.[http://dx.doi.org/10.1093/gerona/glu122] [PMID: 25112493] , 146Bellan M, Guzzaloni G, Rinaldi M, et al. Altered glucose metabolism rather than naive Type 2 Diabetes mellitus (T2DM) is related to vitamin D status in severe obesity. Cardiovasc Diabetol 2014; 13: 57.[http://dx.doi.org/10.1186/1475-2840-13-57] [PMID: 24618074] ]. A recent meta-analysis proved that the inverse association between 25(OH)D3 levels and FPG, as well as HbA1c, is confirmed both in diabetic and in nondiabetic subjects [147Rafiq S, Jeppesen PB. Is hypovitaminosis D related to incidence of type 2 diabetes and high fasting glucose level in healthy subjects: A systematic review and meta-analysis of observational studies. Nutrients 2018; 10(1): E59.[http://dx.doi.org/10.3390/nu10010059] [PMID: 29320437] ]. Furthermore, vitamin D predicts insulin resistance; in fact, 25(OH)D3 plasma concentrations have been inversely related to the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) both in children and in adults [148Mellati AA, Sharifi F, Faghihzade S, Mousaviviri SA, Chiti H, Kazemi SA. Vitamin D status and its associations with components of metabolic syndrome in healthy children. J Pediatr Endocrinol Metab 2015; 28(5-6): 641-8.[http://dx.doi.org/10.1515/jpem-2013-0495] [PMID: 25928755] -150Jackson JL, Judd SE, Panwar B, et al. Associations of 25-hydroxyvitamin D with markers of inflammation, insulin resistance and obesity in black and white community-dwelling adults. J Clin Transl Endocrinol 2016; 5: 21-5.[http://dx.doi.org/10.1016/j.jcte.2016.06.002] [PMID: 27833859] ]. Finally, 25(OH)D3 is directly correlated to 2-hours plasma glucose after an oral glucose tolerance test [151Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004; 79(5): 820-5.[http://dx.doi.org/10.1093/ajcn/79.5.820] [PMID: 15113720] ]. Consistently, a higher prevalence of hypovitaminosis D was reported in diabetic patients compared to healthy controls in different populations [152Tahrani AA, Ball A, Shepherd L, Rahim A, Jones AF, Bates A. The prevalence of vitamin D abnormalities in south asians with type 2 diabetes mellitus in the UK. Int J Clin Pract 2010; 64(3): 351-5.[http://dx.doi.org/10.1111/j.1742-1241.2009.02221.x] [PMID: 19863680] , 153Brock KE, Huang WY, Fraser DR, et al. Diabetes prevalence is associated with serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in US middle-aged Caucasian men and women: A cross-sectional analysis within the prostate, lung, colorectal and ovarian cancer screening trial. Br J Nutr 2011; 106(3): 339-44.[http://dx.doi.org/10.1017/S0007114511001590] [PMID: 21736838] ].

Beside these cross-sectional data, longitudinal studies strengthened the hypothesis that hypovitaminosis D could be detrimental for glucose metabolism. In 2012, Gagnon et al. published the results obtained in the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab), in which baseline and 5-years follow-up data on 11.247 adults demonstrated that higher 25(OH)D3 levels were protective against the development of metabolic syndrome. Interestingly, lower baseline 25(OH)D3 concentrations were predictive of a higher HOMA-IR and FPG after 5 years of follow-up [154Gagnon C, Lu ZX, Magliano DJ, et al. Low serum 25-hydroxyvitamin D is associated with increased risk of the development of the metabolic syndrome at five years: Results from a national, population-based prospective study (the australian diabetes, obesity and lifestyle study: AusDiab). J Clin Endocrinol Metab 2012; 97(6): 1953-61.[http://dx.doi.org/10.1210/jc.2011-3187] [PMID: 22442263] ]. In a pooled analysis of two nested case-control studies conducted on a Finnish population, along a 22-year follow-up period, vitamin D levels were protective against the development of T2DM [155Knekt P, Laaksonen M, Mattila C, et al. Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology 2008; 19(5): 666-71.[http://dx.doi.org/10.1097/EDE.0b013e318176b8ad] [PMID: 18496468] ]; consistently, Forouhi et al. reported an inverse association between baseline 25(OH)D3 levels and the 10-years risk of T2DM development [156Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: The medical research council ely prospective study 1990-2000. Diabetes 2008; 57(10): 2619-25.[http://dx.doi.org/10.2337/db08-0593] [PMID: 18591391] ]. However, these observations were not confirmed in another prospective cohort, when the effect of vitamin D was corrected for other relative determinants [157Mattila C, Knekt P, Männistö S, et al. Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care 2007; 30(10): 2569-70.[http://dx.doi.org/10.2337/dc07-0292] [PMID: 17626891] ].

Taking into account the large number of observations published on this topic in the last few years, while many controversies still exist, there is a predominance of data suggesting a beneficial role for vitamin D in glucose metabolism. However, the mechanisms by which vitamin D regulates glucose homeostasis are only partly understood and many aspects still deserve a deeper insight.

It is now evident that vitamin D is able to both enhance insulin secretion and improve insulin sensitivity. In fact, VDR is expressed by pancreatic cells and 1,25(OH)2D3 is able to directly stimulate insulin secretion [158Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 1980; 209(4458): 823-5.[http://dx.doi.org/10.1126/science.6250216] [PMID: 6250216] , 159Inomata S, Kadowaki S, Yamatani T, Fukase M, Fujita T. Effect of 1 alpha (OH)-vitamin D3 on insulin secretion in diabetes mellitus. Bone Miner 1986; 1(3): 187-92.[PMID: 3334207] ]; moreover, 1,25(OH)2D3 upregulates the transcription of the insulin receptor in vitro [160Maestro B, Molero S, Bajo S, Dávila N, Calle C. Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3). Cell Biochem Funct 2002; 20(3): 227-32.[http://dx.doi.org/10.1002/cbf.951] [PMID: 12125099] ]. As a further clue, different VDR polymorphisms have been identified and some of them have been related to glucose metabolism, with a significant effect determined by geographical belonging. In a recent meta-analysis on 28 studies and 9232 participants evaluating the effect of VDR variants on insulin sensitivity, the association between insulin resistance-related diseases and VDR polymorphisms ApaI, BsmI, FokI variant was confirmed in dark-pigmented Caucasians and Asians, but not in Caucasian with white skin [161DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985; 76(1): 149-55.[http://dx.doi.org/10.1172/JCI111938] [PMID: 3894418] ]. The mechanisms by which VDR regulates the response to insulin are still far from being completely elucidated. However, VDR knock-out in mice muscle cells causes important effects on the insulin signalling. The skeletal muscles account for 80% of insulin-stimulated whole-body glucose disposal [162Han FF, Lv YL, Gong LL, Liu H, Wan ZR, Liu LH. VDR gene variation and insulin resistance related diseases. Lipids Health Dis 2017; 16(1): 157.[http://dx.doi.org/10.1186/s12944-017-0477-7] [PMID: 28822353] ], playing a relevant role in the pathogenesis of insulin resistance. A putative mechanism of action has been recently proposed and it is related to the activity of Forkhead box O1 (FOXO1). FOXO1 is a downstream negative regulator of insulin signalling which, during fasting, promotes gluconeogenesis in the liver. After food intake, FOXO1 activity is inhibited in liver and muscle cells by insulin [163Cheng Z, White MF. Targeting forkhead box O1 from the concept to metabolic diseases: Lessons from mouse models. Antioxid Redox Signal 2011; 14(4): 649-61.[http://dx.doi.org/10.1089/ars.2010.3370] [PMID: 20615072] ]. VDR KO mice develop insulin resistance and glucose intolerance, which are paralleled by increased expression and activity of FOXO1. Moreover, when muscle cell lines are treated with 1,25(OH)2D3 FOXO1 expression and activation are downregulated. Taken together, these findings suggest that: vitamin D regulates insulin signalling in muscle cells and the KO of vitamin D activity leads to the development of insulin resistance; vitamin D action on muscle cells is VDR mediated; a deficient vitamin D signalling induces an increase in FOXO1 activity which can be suppressed by the administration of 1,25(OH)2D3 which, in turn, could be supposed to be a promising therapeutic tool in insulin resistance [164Chen S, Villalta SA, Agrawal DK. FOXO1 mediates vitamin D deficiency-induced insulin resistance in skeletal muscle. J Bone Miner Res 2016; 31(3): 585-95.[http://dx.doi.org/10.1002/jbmr.2729] [PMID: 26462119] ]. There are further data, obtained in animal models, which support the hypothesis that the positive effect of vitamin D on muscle cells can be therapeutically exploited. For example, in mice affected by diet-induced obesity and insulin resistance, the administration of vitamin D significantly improves the response to an oral glucose load and ameliorates the HOMA index; this is related to a direct effect on muscle cells which is paralleled by a reduction of lipid storage and myosteatosis [165Benetti E, Mastrocola R, Chiazza F, et al. Effects of vitamin D on insulin resistance and myosteatosis in diet-induced obese mice. PLoS One 2018; 13(1): e0189707.[http://dx.doi.org/10.1371/journal.pone.0189707] [PMID: 29342166] , 166Jefferson GE, Schnell DM, Thomas DT, Bollinger LM. Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells. J Physiol Biochem 2017; 73(4): 613-21.[http://dx.doi.org/10.1007/s13105-017-0595-8] [PMID: 28980208] ]. Similar data have been obtained on diabetic rats [167Amin SN, Hussein UK, Yassa HD, Hassan SS, Rashed LA. Synergistic actions of Vitamin D and metformin on skeletal muscles and insulin resistance of type 2 diabetic rats. J Cell Physiol 2017.[http://dx.doi.org/10.1002/jcp.26300] [PMID: 29205344] ].

Unfortunately, randomized clinical trials (RCTs) in humans led to conflicting results being therefore absolutely inadequate to support the use of vitamin D as a therapeutic tool for the improvement of glucose metabolism. In fact, recent trials failed to disclose a beneficial effect for vitamin D supplementation on insulin sensitivity in vitamin D deficient overweight/obese [168Mousa A, Naderpoor N, de Courten MP, et al. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: A randomized placebo-controlled trial. Am J Clin Nutr 2017; 105(6): 1372-81.[PMID: 28490514] ] or in diabetic subjects [169Gulseth HL, Wium C, Angel K, Eriksen EF, Birkeland KI. Effects of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with type 2 diabetes and vitamin D deficiency: A randomized controlled trial. Diabetes Care 2017; 40(7): 872-8.[http://dx.doi.org/10.2337/dc16-2302] [PMID: 28468770] -171Krul-Poel YH, Westra S, ten Boekel E, et al. Effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes (sunny trial): A randomized placebo-controlled trial. Diabetes Care 2015; 38(8): 1420-6.[http://dx.doi.org/10.2337/dc15-0323] [PMID: 25972575] ], despite the use of large cholecalciferol doses. Consistently, the weekly administration of 20,000 IU of cholecalciferol was shown to be ineffective in preventing the progression from prediabetes to T2DM in an RCT conducted on 511 patients. In obese subjects, high-dose cholecalciferol administration was recently shown able to selectively increase plasma levels of high-molecular weight adiponectin, a mediator of glucose homeostasis [172Mai S, Walker GE, Vietti R, et al. Acute vitamin D3 supplementation in severe obesity: Evaluation of multimeric adiponectin. Nutrients 2017; 9(5): E459.[http://dx.doi.org/10.3390/nu9050459] [PMID: 28475159] ].

The inconsistency of data from RCTs is reflected in the divergent conclusions obtained by the meta-analysis published on this topic. In fact, a very recent meta-analysis on 24 controlled trials showed a beneficial effect of vitamin D supplementation, at a minimum daily dose of 4000 IU, on FPG, HbA1c and HOMA-IR [173Mirhosseini N, Vatanparast H, Mazidi M, Kimball SM. The effect of improved serum 25-hydroxyvitamin D status on glycemic control in diabetic patients: A meta-analysis. J Clin Endocrinol Metab 2017; 102(9): 3097-110.[http://dx.doi.org/10.1210/jc.2017-01024] [PMID: 28957454] ]; on the contrary the large prevalence of meta-analysis failed to disclose an effect for vitamin D supplementation in T2DM patients [174Krul-Poel YH, Ter Wee MM, Lips P, Simsek S. Management of endocrine disease: The effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Eur J Endocrinol 2017; 176(1): R1-R14.[http://dx.doi.org/10.1530/EJE-16-0391] [PMID: 27484453] ] but also in normoglucotolerant and prediabetic subjects [175Poolsup N, Suksomboon N, Plordplong N. Effect of vitamin D supplementation on insulin resistance and glycaemic control in prediabetes: A systematic review and meta-analysis. Diabet Med 2016; 33(3): 290-9.[http://dx.doi.org/10.1111/dme.12893] [PMID: 26308752] , 176Seida JC, Mitri J, Colmers IN, et al. Clinical review: Effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: A systematic review and meta-analysis. J Clin Endocrinol Metab 2014; 99(10): 3551-60.[http://dx.doi.org/10.1210/jc.2014-2136] [PMID: 25062463] ].

2.4. Vitamin D and Atherosclerosis

Systemic inflammation, glucose metabolism impairment and endothelial dysfunction are well-known risk factors for atherosclerosis; the observation that vitamin D has both an anti-inflammatory activity and a positive effect of endothelial function led many authors to postulate a potential detrimental effect of vitamin D deficiency on the development and the progression of atherosclerotic plaques in vivo. In the last years, many data have been reported in literature, supporting this hypothesis.

Lower 25(OH)D3 levels have been associated with higher IMT and to an increased risk of atherosclerotic plaques, although these findings are controversial and still debated [177Reis JP, von Mühlen D, Michos ED, et al. Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis 2009; 207(2): 585-90.[http://dx.doi.org/10.1016/j.atherosclerosis.2009.05.030] [PMID: 19539290] , 178Deleskog A, Piksasova O, Silveira A, et al. Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2013; 33(11): 2633-8.[http://dx.doi.org/10.1161/ATVBAHA.113.301593] [PMID: 24072691] ]. A possible explanation of these different conclusions could be related to differences in patients selection, being the association more convincing amongst diabetic subjects [179Wang Y, Zhang H. Serum 25-Hydroxyvitamin D3 levels are associated with carotid intima-media thickness and carotid atherosclerotic plaque in type 2 diabetic patients. J Diabetes Res 2017; 2017: 3510275.[http://dx.doi.org/10.1155/2017/3510275] [PMID: 28459072] , 180Lupoli R, Vaccaro A, Ambrosino P, Poggio P, Amato M, Di Minno MN. Impact of vitamin D deficiency on subclinical carotid atherosclerosis: A pooled analysis of cohort studies. J Clin Endocrinol Metab 2017.[http://dx.doi.org/10.1210/jc.2017-00342] [PMID: 28609831] ] than in the general population. Moreover, the correlation between IMT and 25(OH)D3 levels sounds relatively weak and, probably, a large number of subjects is required to disclose this association [181Gjødesen CU, Jørgensen ME, Bjerregaard P, et al. Associations between vitamin D status and atherosclerosis among inuit in greenland. Atherosclerosis 2018; 268: 145-51.[http://dx.doi.org/10.1016/j.atherosclerosis.2017.11.028] [PMID: 29227867] ]. Recently, a meta-analysis published by Lupoli et al. included data from twenty-one studies (3,777 vitamin D-deficit patients and 4,792 controls) evaluating the association between vitamin D and IMT, and 6 studies (1,889 vitamin D-deficient patients and 2,883 controls) evaluating the different prevalence of carotid plaques. According to this analysis, vitamin D deficiency was associated with a higher IMT and an increased prevalence of carotid plaques; the attributable risk for vitamin D deficiency was 35.9%. As previously stated, the risk of carotid plaques seems to be even higher when vitamin D deficiency develops in association with T2DM (OR: 2.29, 95%CI: 1.03-5.11, p=0.043 in general population; OR: 3.27; 95%CI: 1,62-6.62, p=0.001 in diabetic subjects) [180Lupoli R, Vaccaro A, Ambrosino P, Poggio P, Amato M, Di Minno MN. Impact of vitamin D deficiency on subclinical carotid atherosclerosis: A pooled analysis of cohort studies. J Clin Endocrinol Metab 2017.[http://dx.doi.org/10.1210/jc.2017-00342] [PMID: 28609831] ].

Importantly, there is evidence that vitamin D levels are inversely related to the risk of Coronary Artery Disease (CAD). In a large prospective cohort on 1859 patients undergoing a non-urgent coronary angiography, low vitamin D levels were related to the prevalence and severity of CAD [182Nardin M, Verdoia M, Schaffer A, Barbieri L, Marino P, De Luca G. Vitamin D status, diabetes mellitus and coronary artery disease in patients undergoing coronary angiography. Atherosclerosis 2016; 250: 114-21.[http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.019] [PMID: 27205868] ]. The detrimental impact of hypovitaminosis D on the development of CAD seems to be influenced by gender. In fact, hypovitaminosis D seems to be a more relevant risk factor for CAD in females than in males [183Verdoia M, Schaffer A, Barbieri L, et al. Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease. Nutr Metab Cardiovasc Dis 2015; 25(5): 464-70.[http://dx.doi.org/10.1016/j.numecd.2015.01.009] [PMID: 25791862] ]. However, also middle-aged male patients with vitamin D deficiency show and increased risk for coronary artery calcification assessed by computed tomography [184Lee S, Ahuja V, Masaki K, et al. A significant positive association of vitamin D deficiency with coronary artery calcification among middle-aged men: For the era jump study. J Am Coll Nutr 2016; 35(7): 614-20.[http://dx.doi.org/10.1080/07315724.2015.1118651] [PMID: 27315115] ]. It is important to underline that, as per the association with IMT, if on one side many authors agreed in identifying hypovitaminosis D as a risk factor for a more severe CAD [185Dziedzic EA, Przychodzeń S, Dąbrowski M. The effects of vitamin D on severity of coronary artery atherosclerosis and lipid profile of cardiac patients. Arch Med Sci 2016; 12(6): 1199-206.[http://dx.doi.org/10.5114/aoms.2016.60640] [PMID: 27904508] ], according to others, vitamin D levels are not predictive of the extent of atherosclerotic coronary disease [186Dhibar DP, Sharma YP, Bhadada SK, Sachdeva N, Sahu KK. Association of vitamin D deficiency with coronary artery disease. J Clin Diagn Res 2016; 10(9): OC24-8.[PMID: 27790488] , 187Alsancak Y, Cengel A, Akyel A, et al. Relationship between serum vitamin D levels and angiographic severity and extent of coronary artery disease. Eur J Clin Invest 2015; 45(9): 940-8.[http://dx.doi.org/10.1111/eci.12490] [PMID: 26248116] ]. To summarize, although vitamin D has strong pre-clinical data supporting its involvement in the development of atherosclerosis and CAD, clinical data are conflicting and, again, this is the results of the profound differences which distinguish one study from another: the cohorts are generally different for gender and age and for comorbidities, which is particularly relevant if we consider stronger evidence for vitamin D involvement in the pathogenesis of atherosclerosis in diabetic subjects. Recently, an association between 25(OH)D3 levels and cardiovascular risk factors has been observed in patients affected by hypopituitarism, underpinning the potential role of contextual endocrine disorders in strengthening the detrimental effect of hypovitaminosis D [188Savanelli MC, Scarano E, Muscogiuri G, et al. Cardiovascular risk in adult hypopituitaric patients with growth hormone deficiency: Is there a role for vitamin D? Endocrine 2016; 52(1): 111-9.[http://dx.doi.org/10.1007/s12020-015-0779-3] [PMID: 26511949] ]. Moreover, CVDs are the result of a complex pathogenetic model which includes many different risk factors; even in prospective studies, the control of all these elements might be difficult. Finally, different imaging techniques have been used and this is obviously a factor affecting the sensitivity in the detection of subclinical atherosclerosis. Novel imaging techniques, such as intravascular imaging modalities might be considered in the future to better disclose the role of vitamin D in the pathogenesis of CAD. However, at the moment, data are still conflicting and not enough persuasive of the effective role of vitamin D in vivo.

Finally, it is still debated whether the postulated association of vitamin D with coronary and peripheral vascular diseases is the result of hypovitaminosis per se or the effect of secondary hyperparathyroidism accompanying vitamin D deficiency. In fact, serum PTH concentration, but not vitamin D, has been directly associated with IMT in a large cohort of more than 8.000 patients [189Lee YH, Kweon SS, Choi JS, et al. Association of serum vitamin D and parathyroid hormone with subclinical atherosclerotic phenotypes: The dong-gu study. PLoS One 2017; 12(10): e0186421.[http://dx.doi.org/10.1371/journal.pone.0186421] [PMID: 29088221] ]. Similarly, hyperparathyroidism has been associated to the extent of CAD [190Shekarkhar S, Foroughi M, Moatamedi M, Gachkar L. The association of serum parathyroid hormone and severity of coronary artery diseases. Coron Artery Dis 2014; 25(4): 339-42.[http://dx.doi.org/10.1097/MCA.0000000000000089] [PMID: 24487940] ].

Although evidence about the role, in vivo, of hypovitaminosis D as a risk factor for atherosclerosis are inconclusive, there is a general consensus on the significance of vitamin D status as a general marker of good health. In a very recent meta-analysis including almost 27.000 subjects recruited in eight different prospective studies, the global mortality risk significantly increased for lower 25(OH)D3 concentrations [191Gaksch M, Jorde R, Grimnes G, et al. Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium. PLoS One 2017; 12(2): e0170791.[http://dx.doi.org/10.1371/journal.pone.0170791] [PMID: 28207791] ]. Interestingly, hypovitaminosis D was specifically associated with cardiovascular mortality. This observation replicates the results of a very large meta-analysis by Zhang et al., in which a total of 34 publications with 180.667 participants were considered. The authors described an inverse association between plasma 25(OH)D3 concentration and total cardiovascular events and cardiovascular mortality [192Zhang R, Li B, Gao X, et al. Serum 25-hydroxyvitamin D and the risk of cardiovascular disease: Ose-response meta-analysis of prospective studies. Am J Clin Nutr 2017; 105(4): 810-9.[http://dx.doi.org/10.3945/ajcn.116.140392] [PMID: 28251933] ]. However, different trials have tested the effect of cholecalciferol supplementation on cardiovascular health. Specifically, in a trial on 36.282 postmenopausal women randomized to either calcium and vitamin D or to placebo and followed-up for seven years, the treatment had no effect on cardiovascular and cerebrovascular risk [193Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007; 115(7): 846-54.[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.673491] [PMID: 17309935] ]. Similarly, in a subgroup of the same study, calcium/cholecalciferol supplementation seems not to affect the development of coronary artery calcification [194Manson JE, Allison MA, Carr JJ, et al. Calcium/vitamin D supplementation and coronary artery calcification in the women’s health initiative. Menopause 2010; 17(4): 683-91.[http://dx.doi.org/10.1097/gme.0b013e3181d683b5] [PMID: 20551849] ].

On this basis, no recommendations can be made to date for the use of vitamin D supplementation in the prevention and treatment of cardiovascular diseases, as well as for the other extra-skeletal chronic diseases.

CONCLUSION

In conclusion, vitamin D is a pleiotropic hormone, the activity of which is supposed to be much wider than previously known at the cardiovascular level. There is a significant gap between the large evidence relating vitamin D activity to vascular function and healing in vitro, and the relatively poor strength of in vivo data, which are often conflicting and/or inconclusive. While the achievement of a satisfactory vitamin D status can be considered advisable as a general marker of good health, there is still no consensus on the screening and correction of hypovitaminosis D for cardiovascular health.

Large population-based studies are thus required to strengthen the currently available evidence, and to contribute to the understanding of the causal mechanisms underlying the association between vitamin D and cardiovascular health and diseases.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise

ACKNOWLEDGEMENTS

Declared none.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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