Vitamin D and its effects on cell adhesion molecules: A systematic review

doi:10.21203/rs.3.rs-2378202/v1

In order to systematically review the effects of vitamin D supplementation on cell adhesion molecules (CAM), we conducted a systematic search in eletronic databases to identify placebo-controlled randomized clinical trials published through August 2022. The guiding question was: “In diseases whose complications lead to vascular dysfunction and thrombus formation, is vitamin D supplementation associated with CAM concentrations?”. Studies investigating CAM in all age groups of both sexes using any type and dose of vitamin D supplements were included. Of 617 initially obtained articles, 9 met the inclusion criteria. The articles were divided based on clinical outcomes: Cardiovascular Disease (CVD), Type II Diabetes Mellitus (DM-II), Metabolic Syndrome (MS) and Chronic Kidney Disease (CKD). Four articles reported reduced serum CAM concentrations (two with CKD, one with MS and another with DM-II). One of these articles had a two-month interval supplementation protocol (300,000 IU), two had a weekly protocol (50,000 IU), and one had a daily supplementation protocol (2,000 IU). Vitamin D seems to modulate vascular physiology, especially in patients with vitamin D deficiency and CKD. However, the findings of this review do not allow defining appropriate dosages and supplementation models to reduce endothelial dysfunction and CAM concentration.

Biological sciences/Cell biology

Biological sciences/Physiology

Health sciences/Biomarkers

Health sciences/Diseases

Health sciences/Health care

Health sciences/Molecular medicine

vitamin D

antioxidants

inflammation

chronic kidney disease

diabetes mellitus

Cell adhesion molecules (CAM) are glycoproteins expressed on the surface of endothelial cells. CAM are responsible for leukocyte adhesion and transendothelial migration to target tissues, which are essential in several biological events such as cell growth and differentiation, response to infection and inflammation, tissue healing, and immune cell response [1]. CAM are classified into five superfamilies, but three of them are involved in endothelium–leukocyte interactions: integrins (lymphocyte function-associated antigen 1 [LFA-1]; macrophage-1 antigen [Mac-1]; very late antigen 4 [VLA-4]), selectins (L-selectin; P-selectin; E-selectin), and immunoglobulins (intercellular adhesion molecule [ICAM] 1 and 2; vascular cell adhesion molecule 1 [VCAM-1]; platelet and endothelial cell adhesion molecule 1 [PeCAM]; mucosal vascular addressin cell adhesion molecule 1 [MAdCAM-1]). All CAM are involved in the process of leukocyte margination, rolling, adhesion, and transmigration, which are crucial for body immunity. Some studies have also explored the Von Willebrand factor (vWF), a protein synthesized by endothelial cells and stored in Weibel-Palade bodies. When released into the plasma, it acts as a coagulation carrier and mediator of platelet adhesion to injured subendothelium [1, 2].

Under normal conditions, endothelial cells express molecules and receptors that allow immune defense, vascular integrity maintenance, and wound healing [3]. However, this mechanism may be unbalanced in inflammation. The cascade begins with vascular vasodilation, extravasation of plasma proteins as exudate to the interstitium (edema), and leukocyte migration into microcirculation and accumulation at the lesion site [4, 5]. Consequently, osmotic pressure decreases owing to the outflow of high-protein fluid, increased blood viscosity, and reduced blood flow velocity, allowing leukocytes to approach the endothelium more easily [6]. Mediating substances (such as interleukins, histamine, oxygen-derived free radicals, thrombin, platelet-activating factor, endothelin, endotoxin, and tumor necrosis factor-α) produced by the injured tissue lead to endothelial activation, initiating the rolling phase, in which L-selectin is exposed on the leukocyte interacting with endothelium P-selectin, which perform a weak adhesion, allowing leukocyte rolling across the endothelial surface. Subsequently, leukocytes express integrins on their surface, which bind to immunoglobulins (ICAM-1 and VCAM-1). Following this strong adhesion, leukocytes migrate by diapedesis and head to inflammation site [7, 8].

The detection of soluble forms of CAM has been used to predict the severity of several diseases since the expression of these molecules is increased by the amount exacerbated by the stimulus caused by inflammatory cytokines and reactive oxygen species (ROS) formation [9–11]. Thrombus are structures resulting from vascular injury, with an accumulation of platelets, coagulant proteins, and other aggregating factors. In venous thrombus (VT), as a consequence of inflammation, the endothelium is activated, expresses selectins, and stimulates vWF secretion [12–14]. Platelet and leukocyte attachment, tissue factor (TF) expression, and coagulation cascade activation begin. Low blood flow inhibits the protective anticoagulant effect of the endothelium, leading to hypoxia and increased endothelial CAM expression [13]. Some risk factors for VT are obesity, persistent anemias, cancer, and genetic mutations [15].

The decreased exacerbation of chronic inflammatory conditions through antioxidant compounds can be an excellent form of management in these situations. Vitamin D is an important hormone to regulate several cellular mechanisms via antioxidant and anti-inflammatory actions [16]. It can be obtained through exposure to sunlight, foods, or nutritional supplementation. Commonly, vitamin D is associated with bone metabolism, but its function goes far beyond that. Some studies showed a relationship between vitamin D deficiency and the onset or worsen the prognosis of several cardiovascular, autoimmune, musculoskeletal, and psychiatric conditions [17, 18]. Its ability to regulate immune response and oxidative stress has been increasingly explored. Cross-sectional studies show an association between low vitamin D levels and increased viral and bacterial infection severity [19]. Immunomodulation occurs through the suppression of pro-inflammatory cytokine expression and regulation of immune cell activity [20]. Vitamin D stops the differentiation and maturation of dendritic, T, and B cells, increasing IL-10 and reducing IL-12 and IL-17 production, thus reducing exacerbated immune response effects [21].

The active form of vitamin D, 1,25-dihydroxycholecalciferol or calcitriol (1,25(OH)₂D), may exhibit inflammatory activity by influencing endothelial function and CAM expression [22]. Further, serum levels of 25-hydroxyvitamin D (25(OH)D), which indicates the amount of vitamin D in the body, is correlated with endothelial cell activity [23, 24].

Thus, the objective of this systematic review is to evaluate whether vitamin D supplementation can be beneficial in diseases with outcomes related to vascular adhesion and thrombotic events. The findings may help in providing correct nutritional guidance for patients with thrombus.

Search and selection strategy

This systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [25] and the Cochrane Handbook for Systematic Reviews of Interventions [26]. The main guiding question was: “In diseases whose complications lead to vascular dysfunction and thrombus formation, is vitamin D supplementation associated with cell adhesion molecule concentrations?” To delimit the inclusion criteria, the study population, intervention type, comparison type, results, and study type was determined, as shown in Table 1 (PICOS format).

Table 1

Inclusion criteria - PICOS
Parameters	Description
Population (P)	All age groups (children, adolescents, adults, and older people) of both sexes
Intervention (I)	Any type and dose of vitamin D supplements
Comparison (C)	Diet intervention or no intervention (placebo)
Outcome (O)	Diseases with a clinical outcome of thrombosis and/or vascular dysfunction and evaluation of vascular adhesion molecules
Study type (S)	Placebo-controlled randomized clinical trials

In addition to these criteria, only articles in English, using vitamin D exclusively (without co-supplementation), and showing the isolated effect of the substance of interest in the results were included. All articles not meeting these criteria were excluded. The literature was searched from August 5–24, 2022, in the following databases: MEDLINE and EMBASE via Ovid, Web of Science, Scopus, and Cochrane Library. The MeSH terms and keywords ‘vascular cell adhesion molecule’, ‘intercellular adhesion molecule’, ‘cell adhesion molecule’, ‘leukocyte adhesion molecule’, ‘vitamin D’, and ‘randomized controlled trial’ were combined (strategy available in the Supplementary Material).

Selection of Studies

The evaluation was independently performed by two reviewers (JD and MC) through the analysis of the titles and abstracts of all publications resulting from the search strategy. Then, the articles potentially eligible for inclusion were fully read. Once this step was completed, disagreements were resolved by consensus between the reviewers.

Data extraction

The first author (JD) extracted the data using a spreadsheet and the second author (MC) reviewed the extracted data for accuracy and uniformity. Data were selected on the variables study information (authors’ names, year of publication, and country), methods (type of intervention, study design, tools used), sample characteristics (sample size, age, sex), and most relevant results.

Risk of bias assessment and data synthesis

The risk of bias in the selected studies was assessed using the RoB 2, a validated tool to assess the risk of bias in randomized studies recommended by the Cochrane Handbook for Systematic Reviews of Interventions [27]. The determined domains were as follows: 1, bias due to the randomization process; 2, bias due to deviations from intended interventions; 3, bias due to missing outcome data; 4, bias in outcome measurement; and 5, bias in reported outcome selection. A “risk of bias” table summarizes the performance of each study in the aforementioned domains, classifying each study as low, high, and moderate risk of bias.

A narrative synthesis describing the characteristics of the methods, participants, intervention, and the findings from the included studies were conducted because of the lack of methodological homogeneity between studies. The data were organized by ascending year of publication and by summarizing their effects on diseases with thrombotic repercussion/vascular dysfunction.

Study characteristics

The literature search identified 617 records. A total of 436 articles were eligible for abstract reading and 14 were read in full. After full reading, five clinical trials were removed for not meeting the inclusion criteria. Thus, nine articles were included in this review (Fig. 1) [28]. Most studies were judged as having low risk of bias (Fig. 2).

The overall total of participants in all studies was 902 subjects, with 351 men and 551 women. Two studies were conducted only with. The other studies evaluated participants of both sexes, with one study consisting of adult participants and the others including adults and older people. Only one study used intramuscular administration of vitamin D, and the others had oral administration. The outcome diseases evaluated were cardiovascular diseases (CVD), type II diabetes mellitus (DM-II), metabolic syndrome (MS) and chronic kidney disease (CKD). To facilitate the understanding and discussion of the studies, they were presented by type of disease. Of the studies selected, four showed improved serum CAM concentrations (two in CKD, one in MS, and another with DM-II), all of them with oral supplementation, one using a two-month interval supplementation protocol (300,000 IU), two with a weekly protocol (50,000 IU), and one with daily supplementation (2,000 IU). Supplementation time ranged from 8–16 weeks. Two of the four studies that presented satisfactory results in reducing CAM used the previous classification of vitamin D deficiency as an inclusion criterion (Table 2). Vitamin D level has been a clinical strategy to assess the risk of progression in several diseases. However, the conditions under which these supplementations take place may be the key to understanding the results found in the literature.

Table 2. Study Characteristics with vitamin D supplementation

Reference	Population* /Methods**		Objectives	Dosage/ Duration	Outcomes
Cardiovascular Diseases
WITHAM et al., 2012	75 patients with a history of myocardial infarction.	Two groups: intervention (n=39) and placebo (n=36).	Evaluated whether vitamin D supplementation could improve endothelial function and other markers of vascular function (Reactive hyperaemia index, blood pressure, cholesterol, Hs-CRP, vWF, TNF-α, e-selectin, BNP, thrombomodulin and 25(OH)D.	Oral supplementation with 100,000 IU vitamin D3 or placebo (identical appearance) at baseline, 2 months and 4 months.	25(OH)D levels increased in the intervention group relative to placebo (+13 vs +1 U/L, p= 0.04), but showed no differences in E-selectin (+2.7 vs +1.6 U/L, p= 0.42) and vWF (+6.3 vs +12.4 nmol/L, p= 0.77). It concluded that vitamin D supplementation did not improve endothelial function in the evaluated subjects.
WOOD et al., 2012	265 healthy postmenopausal women.	Three groups: intervention I (400 IU - n=84), intervention II (1000 IU - n=90) and placebo (n=91).	Evaluated if daily doses of vitamin D3 affected conventional markers of cardiovascular disease (CVD) risk: serum lipid profile, insulin resistance, Hs-CRP, IL-6, ICAM-1 and blood pressure.	Oral supplementation with daily capsules of 400 or 1,000 IU vitamin D3 or placebo (identical appearance) for a year.	25(OH)D levels increased in the intervention group relative to placebo (400IU = +33,0/1000IU = 42,9/ plac = -2,72/ p=0,001). Median concentrations of ICAM-1 (400IU = -0,001/1000IU= +0,01/ plac = +0,003/ p=0,67)and other cardiovascular parameters were unaffected by study treatment. Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors.
SOKOL et al., 2012	90 patients with coronary artery disease (CAD) presenting vitamin D deficiency.	Two groups: intervention (n=48) and placebo (n=48)	Investigated the effects of vitamin D repletion on endothelial function and inflammation (ICAM-1, VCAM-1, e-selectina, IL-6, IL-12, hs-CRP, IFN-γ, chemokine CXCL-10 and blood pressure).	Oral supplementation with 50,000 IU of vitamin D2 or placebo (identical appearance), weekly, for 12 weeks.	25(OH)D levels increased in the intervention group (between-group difference = 22 ng/ml, p < 0.001). Within-group and between-group differences in ICAM-1 levels were greater with placebo (between-group difference = 6 ng/ml, p = 0.048). VCAM-1 levels decreased in both groups by a similar magnitude (median difference between groups = 8.5 ng/ml, p = 0.79). No significant differences in e-selectin (median difference between groups = -1,0 ng/ml, p = 0.95) and other cardiovascular parameters were found with treatment. Repleting vitamin D levels in subjects with CAD failed to demonstrate any benefits on surrogate markers of cardiovascular health.
Type 2 diabetes mellitus / metabolic syndrome
DALAN et al., 2016	64 patientes with T2-DM presenting vitamin D deficiency.	Two groups: intervention (n=33) and placebo (n=31)	Evaluated endothelial function and vascular biomarkers: peripheral tonometry, e-selectin, vWF and hs-CRP.	Patients with 25(OH)D concentration ⩽20 ng/mL = 4,000 IU of vitamin D3 or placebo (identical)/daily. Patients with 25(OH)D concentration 21–30 ng/mL = 2,000 IU of vitamin D3 or placebo/daily. Duration: 16 weeks.	With adjusting for baseline variables, there was no statistically significant change for the e-selectin selectin (-1.4vs -6.1/ p= 0.32) and vWF selectin (+6.0 vs +4.0/ p= 0.70). Therefore, vitamin D supplementation for 16 weeks resulted in a slight but not significant improvement in endothelial function in patients with T2-DM.
TALASAZ et al., 2018	112 women with T2-DM and ischemic heart disease.	Two groups: intervention (n=55) and placebo (n=57).	Investigated whether a single parenteral dose of 25(OH) Vit D could improve the endothelial function in T2-DM patients with ischemic heart disease	A single dose of either vitamin D3 (300,000 IU) or a matching placebo, intramuscularly, for 8 weeks.	In the supplemented group, the level of serum 25(OH) D was increased significantly when compered to placebo (29.6 ± 20.8 vs. 44.5 ± 19.2 ng/mL; P < 0.05). Within the supplemented group, before and after vitamin D intervention no significant changes in the levels of ICAM-1 (624.1 ± 269.8 vs. 588.3 ± 247.23 ng/mL) and VCAM-1 (1812.2 ± 641.2 vs. 1726.7 ± 637.2 ng/mL) were observed.
QASEMI et al., 2021	44 patients with T2-DM and hypertension.	Two groups: intervention (n=23) and placebo (n=21).	Evaluate the effect of vitamin D supplementation on ﬂow-mediated dilatation (FMD), oxLDL and ICAM-1	Oral supplementation with one daily capsule containing 2,000 IU of vitamin D3 or matched placebo capsule, for 12 weeks.	In the intervention group serum level of vitamin D increased (32.42 ± 10.56 to 40.45 ± 12.94 / p < 0.001). oxLDL and ICAM-1 were significantly lower when compared to their baseline (1286.09 to 592.61 p< 0,001) and when compared to the placebo group (p=0,006).
SALEKZAMANI et al., 2017	71 patients with metabolic syndrome – MS.	Two groups: intervention (n=35) and placebo (n=36).	Evaluated if supplementation with vitamin D improves the endothelial function and vascular biomarkers (IL-6, hs-CRP, VCAM-1, e-selectin, and common carotid intima media thickness).	Patients received vitamin D3 (50,000 IU/ week) or matching placebo for 16 weeks.	Vitamin D3 supplementation improved some proatherogenic inflammatory markers in subjects with metabolic syndrome. No changes of hs-CRP and carotid intima media thickness were shown. The mean concentration of VCAM-1 and e-selectin were significantly decreased by −3.69 and −2.18% in the intervention group, respectively (p = 0.007, p = 0.023) after 16 weeks.

Chronic kidney disease

NAEINI

et al., 2016

64 patients with end-stage renal failure (ESRD) presenting vitamin D deficiency.

Two groups: intervention (n=32) and control (n=32).

Evaluated the effect of vitamin D administration on ICAM-1 and VCAM-1 serum levels in ESRD patients on hemodialysis.

Oral supplementation with 50,000 IU vitamin D3 or placebo (identical), weekly for 12 weeks and then treatment was continued for 3 months with the same dose every 3 weeks.

The change in serum level of 25(OH)D was significant in the treatment group. Serum levels of ICAM (1292.5±316.7 vs. 14445.6±481.3 <0.001) and VCAM (8843.3±1858.8 vs. 9345.7±1465 <0.001) also changed significantly in the treatment group when compared to control. Vitamin D administration in ESRD patients reduces serum levels of ICAM and VCAM which might improve the vascular condition of these patients.

KUMAR

et al., 2017

117 patients with nondiabetic chronic kidney disease (CKD) stage 3–4 and vitamin D deﬁciency.

Two groups: intervention (n=58) and placebo (n=59).

Investigated the effect of vitamin D supplementation on vascular function (PWV, e-selectin, vWF, hs-CRP and IL-6).

Oral doses of vitamin D3 (300,000 IU) or placebo, bimonthly, for 16 weeks.

Vitamin D3 supplementation signiﬁcantly increased endothelium-dependent brachial artery ﬂow-mediated dilation at 16 weeks and favorable changes in PWV and circulating IL-6 levels. E-selectin showed a statistical difference in the supplemented group (24.71 [28.89 to 25.25], p=0.03), when compared to its baseline, but with no difference with the placebo group. The vWF did not show intragroup and intergroup differences.

* Participants whose data made up the final results of each study. ** Double-blind, randomized, placebo-controlled, parallel group studies. Hs-CRP – high sensitivity C reactive protein; vWF – von-Willebrand Factor; TNF-α – Tumoral necrosis factor; BNP - B-type natriuretic peptide; IL-6 – Interleukin-6; ICAM-1 - intracellular adhesion molecule-1; VCAM-1 – vascular cell adhesion molecule-1; IFN-γ - interferon-gamma; T2-DM - type II diabetes mellitus; 25(OH)D – 25 hidroxivitamin D; PWV - pulse wave velocity; oxLDL - oxidized

Cardiovascular diseases

Among the cardiovascular disease studies identified in this review, vitamin D supplementation did not reduce CAM concentrations. In the study conducted by Witham et al. (2012) [29], participants who were supplemented with 100,000 IU of vitamin D3 in three moments (initial time, two months, and four months) had CAM concentrations evaluated. In this study, initial vitamin D status was not considered as inclusion or exclusion criteria. Vitamin D supplementation did not significantly affect E-selectin and vWF concentrations, although its serum concentrations increased. One study considered vitamin D deficiency (25(OH)D concentrations ≤ 20 ng/mL) as an inclusion criteria [30]. Wood et al. (2012) [31] used two doses of vitamin D supplementation (400 and 1,000 IU/day for one year) and analyzed soluble intercellular adhesion molecule-1 (sICAM-1) concentrations as an outcome. Although vitamin D status improved, median concentrations of ICAM-1 and other cardiovascular parameters were unaffected by the study treatment. Additionally, Sokol et al. (2012) [30] used the supplementation of 50,000 IU vitamin D/week over 12 weeks in adult subjects, with a greater focus on endothelial function and inflammation. However, soluble vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin concentrations exhibited no significant improvement, whereas the placebo group showed reduced sICAM-1 concentration.

Diabetes mellitus II and Metabolic syndrome

Based on the inclusion criteria of this review, three studies on DM-II were selected. Dalan et al. (2016) [32] included 64 patients with DM-II and hypovitaminosis D who were supplemented with vitamin D (4,000 IU/day for 25(OH)D < 20 ng/mL; and 2,000 IU/day for 25(OH)D ≥ 20–30 ng/mL) for 16 weeks. Vitamin D supplementation was safe and effective; however, no significant difference was observed in E-selectin, which was the only CAM studied. Qasemi et al. (2021) [33] included participants with DM-II and systemic arterial hypertension who received 2,000 IU/day for 12 weeks. Vitamin D concentrations increased in the supplemented group, but not enough to restore it to the minimum adequate level (≥ 20 ng/mL). ICAM concentration decreased significantly in the supplemented group. The study by Talasaz et al. (2018) [34] reported no changes in ICAM and VCAM concentrations after supplementation with a single intramuscular dose of 300,000 IU and evaluation after eight weeks.

The study by Salekzamani et al. (2017) [35] performed with MS patients used 50,000 IU/week supplementation for 16 weeks and observed reduced E-selectin concentrations in the supplemented group compared to baseline, but not compared to the placebo group. However, VCAM showed no difference neither in intragroup comparison nor to the placebo.

Chronic kidney disease

The two selected articles on CKD used vitamin D deficiency as an inclusion criterion. Naeini et al. (2016) [36] adopted a cutoff point of 25(OH)D > 30 ng/mL for the classification of vitamin D deficiency, according to the Endocrine Society (ENDO), International Osteoporosis Foundation (IOF), National Osteoporosis Foundation (NOF), and American Geriatrics Society (AGS) [37, 38]. In this study, satisfactory results were observed in the efficacy of supplementation with 50,000 IU/week for 12 weeks, with a significant reduction in ICAM and VCAM concentrations compared to the placebo group. Kumar et al. (2017) [39] used concentrations less than 20 ng/mL (IOM, 2011) as a parameter for vitamin D deficiency and reported that after 16 weeks of supplementation (300,000 IU every 8 weeks), E-selectin concentrations decreased in the supplemented group compared to baseline, but showed no different concentrations compared to the placebo group. They also evaluated vWF, but there was no difference post-supplementation.

Using vitamin D deficiency as a selection criterion, Naeini et al (2017) [36] e Kumar et al (2017) [39] identified reduced serum CAM concentrations, and others studies did not identify any reduction [33, 35]. Although the controversial results, many studies show that supplementation is more effective (regardless of the outcome studied) in people with high needs [40–42]. A recently published consensus recommends that individuals be screened for initial vitamin D status before supplementation [43].

A wide variation in supplementation dosages was observed among the studies. In most studies, the frequency of supplement use was daily [31, 32, 33] or weekly [30, 35, 36], but in some of them the use was bimonthly [29, 39] or a single dosage was adopted [34]. The absence of a maximum recommendation for weekly, monthly, or even single overdose periods leads to a reflection on the threshold between what is beneficial and harmful to health. In one of the studies included in this review, an intramuscular megadose was used, but the changes in CAM concentrations were not reported [34]. In most studies where CAM levels were reduced successfully, a high-dose oral vitamin D supplementation for longer intervals was used [35, 36, 39]. However, Qasemi et al. (2021) [33] observed reduced sICAM-1 concentrations using a lower daily dosage for 3 months. Possibly, larger doses (in bolus) seem to ensure treatment adherence, as they are almost always administered in an environment with a person responsible for the supply. However, this strategy may lead to errors in result interpretation, because vitamin D concentrations may increase substantially in a short time and then decrease until the next dose is administered. In contrast, daily doses will lead to a long-term but safe response, as they are less likely to cause toxicity. Moreover, toxicity can lead to severe and prolonged hypercalcemia, resulting in serious health consequences [44, 45]. Among the studies in which the participant was responsible for taking the oral supplement, only two did not report data on adherence [29, 34]. Verification of adherence is important to better understand the type of data obtained. These two studies did not report any reduction in serum CAM concentrations.

The prevalence of CKD, a disease with high morbidity and mortality, has been increasing worldwide. It increases the risk of CVD and other noncommunicable chronic diseases (NCDs). It is estimated that about 13.4% of the entire population has CKD, and those who are in advanced stages of the disease (requiring transplantation) are estimated between 4.902 and 7.083 million [46]. Calcium-phosphorus imbalance and vitamin D deficiency are common in CKD. Multiple mechanisms may be involved, such as increased proteinuria, the uremic epidermis (impairing sunlight uptake and subsequent conversion of 7-dehydrocholesterol into vitamin D), and restrictive diets [47]. The present review identified reduction of CAM concentrations in the vitamin D supplemented groups in CKD studies [36, 39]. The kidney is the main organ responsible for producing the active form of vitamin D, and one of the main mechanisms through which CKD is associated with its deficiency is the reduced availability of 25(OH)D due to reduced glomerular filtration. Thus, with greater supply via supplementation, the active metabolite could meet the demands for endothelial reestablishment and reduce vascular stress [48]. This improvement was also observed in a clinical study on CKD patients, with reduced E-selectin, ICAM, VCAM, and vWF levels [49].

The World Health Organization estimated that approximately 23.6 million people will die from CVD-related causes by 2030 [50]. Several studies show an inverse association between vitamin D status and morbidity and mortality in CVD [51–54] as 1,25(OH)2D reduces vascular calcification, regulates the renin-angiotensin-aldosterone system, and exhibits immunomodulatory action, thereby reducing inflammation [55–57]. In the CVD studies identified in this review, only one investigated the effect of supplementation in people with vitamin D deficiency [30]. However, in the referred study Sokol et al. (2012) used vitamin D2 as a supplement, which is known to be less effective in increasing serum 25(OH)D concentrations [58] and could possibly explain their negative results. Although vitamin D deficiency is associated with an increased risk of CVD and coronary atherosclerosis severity [59], no differences were observed in CAM concentrations in any of the CVD case studies.

Similar to CVDs, DM-II is one of the most prevalent diseases worldwide. The number of people affected by this disease has been estimated to increase by 10.8% by 2040 [60]. Generally, chronic hyperglycemia affects the vascular environment, including larger vessels and the microvasculature, leading to the classic symptoms of diabetes, such as retinopathy, diabetic nephropathy, and neuropathy; which reduces the quality of life of the patients [61]. Vitamin D indirectly affects carbohydrate and lipid metabolism, insulin secretion and resistance, and obesity [62–64]. In vitro and in vivo studies have demonstrated the potential of vitamin D in protecting the vascular endothelium, because it reduces oxidative stress by modulating the inflammatory response and platelet activation, thereby reducing the expression of vascular endothelial CAM [65, 66]. Studies on patients with DM-II and MS showed reduced E-selectin [35] and ICAM [33] concentrations in the vitamin D supplemented group. E-selectin participates in leukocyte recruitment and light adhesion stage, and its expression on the endothelium indicates pro-inflammation [67]. The common points in these diseases are the presence of inflammation and endothelial dysfunction, which lead to a marked increase in CAM expression, which, depending on the lesion, may cause thrombus development.

Vitamin D seems to play an important role in vascular physiology, as some studies showed that vitamin D supplementation reduced CAM concentrations, especially in patients with CKD and vitamin D deficiency. Nevertheless, considering the findings of this review and the controversial results, it was not possible to define appropriate dosages and supplementation models to reduce endothelial dysfunction and CAM concentration. The scarcity of studies involving vitamin D supplementation and its effects on CAM concentrations in the same disease and the inherent complexity of each pathology limit a unified conclusion.

Acknowledgements: The authors thank the excellent technical assistance provided by Dr. Joana Pereira and Viviane Fernandes.

Author Contributions: JDCM and TS were responsible for designing, writing and reporting the review protocol, conducting the search, screening potentially eligible studies, extracting and analyzing data, interpreting results, and creating ’Summary of findings’ tables. CSCR contributed to writing the report and interpreting results. CCC designed the review protocol, she contributed to writing the report, analyzing data and interpreting results. MC was responsible for designing the review protocol and screening potentially eligible studies. She was responsible to drafting the manuscript, analyzing data and interpreting results.

Funding

This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (MC, process# 408401/2017-6); Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (process number E-26-202.213/2018).

Competing Interests

No potential conflict of interest was reported by the authors.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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No competing interests reported.

Supplementarytable.docx

Vitamin D and its effects on cell adhesion molecules: A systematic review

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Search and selection strategy

Selection of Studies

Data extraction

Risk of bias assessment and data synthesis

Results

Study characteristics

Cardiovascular diseases

Diabetes mellitus II and Metabolic syndrome

Chronic kidney disease

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1