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Vitamin D concentrations, endothelial progenitor cells, and cardiovascular risk factors

  • Medistem Panama Inc.


Our study aimed to establish the association of vitamin D status with the level of circulating endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs) and to demonstrate the effect of vitamin D on the level of lipoproteins responsible for increased cardiovascular risk and high blood pressure. 41 healthy adults were selected. EPCs were defined as CD34+/KDR+ cells, and CACs were defined as cells that expressed endothelial markers after incubation of mononuclear blood cells with endothelial growth factors during 5 days. We found a positive association between EPCs, CACs and the level of vitamin D and an inverse correlation between several subclasses of lipoproteins. The level of vitamin D higher than 40 ng/ml demonstrated a positive effect on regulation of blood pressure, and there was significant difference in cholesterol/HDL ratio, very low-density lipoproteins, and triglycerides for groups of subjects with varying levels of vitamin D.
PANMINERVA MED 2010;52(Suppl. 1 to No. 2):1-7
Vitamin D concentrations, endothelial progenitor cells,
and cardiovascular risk factors
Our study aimed to establish the association of vitamin D sta-
tus with the level of circulating endothelial progenitor cells
(EPCs) and circulating angiogenic cells (CACs) and to demon-
strate the effect of vitamin D on the level of lipoproteins respon-
sible for increased cardiovascular risk and high blood pres-
sure. 41 healthy adults were selected. EPCs were defined as
CD34+/KDR+ cells, and CACs were defined as cells that
expressed endothelial markers after incubation of mononu-
clear blood cells with endothelial growth factors during 5 days.
We found a positive association between EPCs, CACs and the
level of vitamin D and an inverse correlation between several
subclasses of lipoproteins. The level of vitamin D higher than
40 ng/ml demonstrated a positive effect on regulation of blood
pressure, and there was significant difference in choles-
terol/HDL ratio, very low-density lipoproteins, and triglyc-
erides for groups of subjects with varying levels of vitamin D.
:Endothelial progenitor cells, Vitamin D, cardiovas-
cular risk factors.
he purpose of this study was to establish the asso-
ciation of vitamin D status with the level of cir-
culating endothelial progenitor cells (EPCs). Vitamin
D deficiency is a common condition, presentin approx-
imately 30% to 50% of the general population. Low 25-
hydroxyvitamin D levels may have an effect on car-
diovascular health, cancer, and diabetes.1-9
Studies on the connection between ischemic heart
disease, hypertension and vitamin D are conflicting.
Some studies found an inverse relationship between
levels of the active form of vitamin D, blood pressure,
and plasma renin activity. 10, 11 Another study report-
ed a positive association.12
Because the vitamin D receptor (VDR) is present in
most cells, vitamin D has a wide rangeof therapeutic
and health-related benefits. The active form of vitamin
D3 is a steroid hormone shown to regulate more than
60 genes.13,14 The translocation of 1α,25(OH)2D3 into
cells, where it binds with high affinity to vitamin D
nuclear receptors, results in altering rates of gene
expression. By this pathway, the active form of vitamin
D influences a number of genes relevant to arterial
wall functions. These include VEGF, matrix metallo-
proteinase, myosin, and structural proteins. Vitamin D
receptors are densely distributed in theendothelium,
and vitamin D3modulates vasculartone by reducing
calcium influx into the endothelial cells. 1,25(OH)2D
is a veryeffective modulator of the immune system. In
animal models, it has been demonstrated that pre-
treatment with 1,25(OH)2Dis effective in preventing
the onset of type 1 diabetes, multiple sclerosis, rheuma-
toid arthritis,and Crohn’s disease.15
Our goal was to prove that optimal levels of vitamin
D could be correlated with the increased number of cir-
culating EPCs and angiogenic cells. The number of
1Center for the Improvement
of Human Functioning International, Inc.
Bio-communication Research Institute Division
Wichita, KS, USA
2Irvine3 Vascular Labs, CH-PE University, Pescara, Italy
Acknowledgments.—This research was supported in part by Allan P.
Corresponding author: N. A. Mikirova, PhD, Center for the Improvement
Human Functioning International, Inc., Bio-communication Research
Institute Division, 3100 N. Hillside, Wichita, KS 67219, USA.
Vol. 52 - Suppl. 1 to No. 2 PANMINERVA MEDICA 1
circulating EPCs in an individual’s blood may be an
indicator of overall vascular health. In atherosclerosis,
the endothelial layers may become damaged, and near-
by endothelial cells are recruited to help repair vessels
or form new ones. EPCs are generated from bone mar-
row and contribute to repair of the endothelium. A
lack of EPCs can lead to vascular dysfunction and a
progression of atherosclerosis. There are no systematic
studies regarding the physiological variation in the
number or the lifetime of EPCs in physiological or
pathological conditions.16 The effect of cardiovascu-
lar risk factors, diabetes, acute myocardial infarction
and vascular trauma on the number of EPCs has been
described in several studies.17-21 In a large popula-
tion–based study it was shown that there was a posi-
tive relation between EPC numbers and vascular risk
factors and a positive association of EPCs with
Framingham risk factors.22
Our focus was to evaluate if the population of EPCs
could be correlated with vitamin D status. The levels
of EPCs and the level of angiogenic cells developed
from PBMSc in vitro were measured and compared
with the level of vitamin D in serum.
Materials and methods
Study population and methods
Forty-one adults ages 23-74 were included.
Exclusion criteria were hypertension (use of anti-
hypertensive therapy), diabetes mellitus, and a histo-
ry of neoplasm or active cancer. The study was
approved by the Institutional Review Board commit-
tee, and informed consent was obtained from all sub-
jects. Fasting serum and blood samples were taken
and analyzed within 4 hours of collection. The serum
was used for measurements of the lipid profile (total
cholesterol, high-density lipoprotein cholesterol (HDL),
low-density lipoproteins (LDL), triglycerides, very
low-density lipoproteins [VLDV]), glucose, and C-
reactive protein by established clinical laboratory tests.
Blood pressure was measured for each participant on
the same day. Serum level of vitamin D (25(OH)D) was
determined by radioimmunoassay (RIA kit, DiaSorin,
Stillwater, MN). Blood circulating progenitor cells
were phenotyped and quantified by flow cytometric
analysis. Blood collection was taken at the same time
(8-10 a.m.), as there are indications that the number of
EPCs exhibit diurnal variations with an increase
between 3 pm and 10 p.m.22 All participants were
asked to stop taking vitamin D at least one week before
blood drawing.
Method of measurements of endothelial progenitor
EPCs have been identified as a circulating cell pop-
ulation in peripheral blood that co-expresses
hematopoietic stem/progenitor cell markers (CD34 or
AC133) as well as endothelial markers (VE-Cadherin
or VEGFR-2). These cells may augment the injury-
repair process and promote angiogenesis.23, 24
The level of peripheral blood progenitor cells was
analyzed by the expression of cell-surface antigens
with direct 2-color cytometric analysis using fluores-
cein isothiocyanate (FITC)-conjugated and phyco-
erythrin (PE)-conjugated monoclonal antibodies
(mAbs). To measure EPCs, the peripheral blood
mononuclear cells were isolated from peripheral blood
using density-gradient centrifugation. Separated
mononuclear cells were labeled for 20 to 30 min at
4°C using manufacturer-recommended concentrations
with antihuman-KDR-PE (Becton Dickinson, San
Diego, California) and antihuman-CD34-FITC
(Miltenyi Biotec, Auburn, CA, USA). Fluorescent iso-
type-matched antibodies were used as controls. Cell
fluorescence was measured immediately after staining.
A morphological gate included lymphocytes and
monocytes. Circulating EPCs were defined as CD34+/
KDR+ cells.
Method of measurement of angiogenic cells
In addition to the population of circulating EPCs
defined by a specific stem/progenitor cells marker, we
measured the level of angiogenic cells after culturing
mononuclear cells on fibronectin in an endothelial
medium. This cell population was defined as circu-
lating angiogenic cells (CACs)25, 26 and expresses
monocyte/macrophage markers and markers of
endothelial cells. The population includes endothelial
cells, endothelial progenitor cells and cells-expressed
monocyte /macrophage markers. To find the number
of CACs, mononuclear cells were plated in an EBM-
2 medium supplemented with endothelial growth fac-
tors on fibronectin-coated 6-well plates for 5 days.
Adherent cells were detached and stained for markers
of endothelial cells: KDR, CD144, CD105, and
CD62E. In addition, a portion of the cells was incu-
Vol. 52 - Suppl. 1 to No. 2 PANMINERVA MEDICA 3
bated with Dil-labeled acLDL (Molecular probe) and
with FITC-labeled Ulex europaeus agglutinin I (ulex-
lectin, Sigma). Morphological analysis of these cells
after 5 days of culture of the mononuclear cells demon-
strated that some cells developed elongated, spindle-
shaped and fibroblast-like morphology after adhesion
to the plate.
Statistical analysis
The data were analyzed by Systat software (Systat,
Inc) and Kaleidagraph software. Variables were pre-
sented as mean values ± SD, or as medians with cor-
responding 25th percentiles. Association of EPCs with
the level of vitamin D and vascular risk factors was
assessed using linear models. Statistical significance
was accepted if the null hypothesis could be rejected
at P0.05.
Positive correlation of EPCs, angiogenic cells, and
vitamin D
The study sample was a representation of the healthy
general population. Baseline characteristics of partic-
ipants are shown in Table I (average, minimal, and
maximal values of the age and clinical tests). The mean
25(OH)D concentration for all participants was 29.8
ng/mL. The percentage of participants with a level of
vitamin D less than 20 ng/mL, which is considered
deficient, was 36%. A plasma level of vitamin D in
the range 20-30 ng/mL was considered as insufficient,
and sufficient levels were greater than 30-40 ng/mL.
Optimal levels are between 40-80 ng/mL. Other para-
meters included in Table I are conventional cardio-
vascular risk factors and the level of glucose.
The effect of vitamin D status and risk factors on the
number of circulating EPCs and cultured angiogenic
cells was analyzed for all study subjects. The number
of EPCs measured in circulation was determined as
CD34+/ KDR+ cells. The mean number of EPCs in
PBMCs in the gating area that excluded granulocytes
was (0.05±0.03%). To prove that vitamin D had an
effect on the level of endothelial progenitor cells in
circulation, the values of measured CD34/KDR pos-
itive cells were compared for subjects with a level of
vitamin D higher and lower than sufficient levels.
The distributions of EPCs for the levels of vitamin
D higher and lower than 40 ng/mL are shown in Figure
1. The mean percentage of EPCs for subjects with a lev-
el of vitamin D lower than 40 ng/mL was significant-
ly different than the mean percentage of EPCs for sub-
jects with a level of vitamin D higher than 40 ng/mL
(0.045 versus 0.068, P value for trend <0.01). Mean val-
ues of EPCs for the levels of vitamin D less or higher
than 30 ng/mL were 0.046 and 0.060 respectively
A positive correlation was found between CACs
and the level of vitamin D. For development of CACs,
mononuclear cells were placed on fibronectin-coated
plates in a medium with several growth factors: vas-
TABLE I.—Participants’characteristics.
Average Min Max Units
Age 49.65 20 76
Cholesterol 205.56 141 277 mg/dL
Cholesterol/HDL Ratio 3.58 2 6.3
LDL 114.05 47 164 mg/dL
CRP 3.15 0.11 16.63 mg/L
Glucose 100.73 79 198 mg/dL
HDL Cholesterol 62.12 35 124 mg/dL
LDL/HDL Ratio 2.00 0.9 3.6
Triglycerides 143.26 48 457 mg/dL
Vitamin D 29.82 6 60 ng/mL
VLDL 27.1 10 60 mg/dL
Systolic pressure 123.90 92 158 mmHg
Diastolic pressure 73.85 58 96 mmHg
Distribution of EPCs for levels of vitaminaD
lower and higher than <10 ng/mL
Vitamin D <40 ng/mL Vitamin 40 ng/mL
Figure 1.—Distribution of EPCs for the levels of vitamin D lower and
higher than 40 ng/mL. Each box encloses 50% of data with the median value
of the variable.
cular endothelial growth factor (VEGF), fibroblast
growth factor (FGF), epidermal growth factor (EGF)
and insulin-like growth factor (IGF). After 5 days of
exposure to growth factors, attached cells were ana-
lyzed for the presence of endothelial markers. The
angiogenic origin of cultured cells was demonstrated
by expression of VEGF R2 (KDR), CD105, CD62E
and CD144. The expression of these endothelial mark-
er proteins on adherent cells was measured by flow
cytometry. In addition, cells were double stained by
Dil- ac-LDL and lectin. Most of the cells from the
population of attached cells were positive for endothe-
lial markers. The percentage of KDR, CD105, and
CD62E –positive cells was 50% -100% in the gated
region, which included large elongated cells, and 15%-
50% in all attached cells. The expression of CD144 was
lower than 10% for all measured samples.
Because these types of cells participate in vascular
repair and angiogenesis, we further characterized the
effect of vitamin D on the ability of cultured mononu-
clear cells to differentiate to angiogenic cells. The per-
centage of cells differentiated in angiogenic cells in a
medium with endothelial growth factors was com-
pared with the measured levels of vitamin D in the
blood for all participants. The number of CACs demon-
strated a positive association with the level of vitamin
D. Percentage of the total attached cells expressing
KDR was 21% and 34% for the levels of vitamin D less
and higher than 40 ng/mL (P<0.05). For the cells count-
ed in the gated region of 10-14 uM size cells, these
values were 74% (vitamin D < 40 ng/mL) and 89%
(vitamin D? 40ng/ml) with P<0.02.
The same results were found for the population of
cells expressing CD105 and CD62E. The percentage
of cells stained positive for CD62E was 72% for lev-
els of vitamin D less than 40ng/mL, and 89% for lev-
els of vitamin D higher than 40ng/ml. Mean percent-
age of CD105 positive cells from attached cell popu-
lation was increased from 77% to 95% for subjects
with an insufficient or deficient level of vitamin D in
comparison to the subjects with a sufficient level of vit-
amin D. In addition, cultured cells were double stained
by Dil-Ac-LDL and lectin and showed that 50%±24%
of attached cells were stained positive.
Factors that have an inverse correlation with the num-
ber of circulating endothelial progenitor cells
After characterization of the endothelial progeni-
tor cells by expression of CD34 and VEGF receptor
(KDR), the percentage of these cells in circulation
was compared with all other measured parameters:
lipid profile, C-reactive protein, level of fasting glucose,
and blood pressure. We first investigated whether there
was a correlation between the level of EPCs in blood
and the level of several subclasses of lipoproteins. For
many subclasses of lipoproteins, clinical tests gener-
ally focus on the following types: high-density lipopro-
teins (HDL), which transport cholesterol away from
arteries and are protective; low-density lipoproteins
(LDL), which can penetrate the arterial wall and deposit
cholesterol within the artery, thus contributing to heart
disease; and very-low-density lipoproteins (VLDL),
TABLE II.—Average values of EPCs for the levels of test parameters higher and lower than the risk levels.
Parameter Test values lower Percentage Test values higher Percentage P for trend
than borderline of EPCs than borderline of EPCs (one-sided)
Glucose <100mg/dL 0.061 >100 mg/dL 0.044 0.020
VLDL <30 mg/dL 0.061 >30 mg/dL 0.035 0.001
Systolic pressure <140 mmHg 0.060>140 mmHg 0.0400.010
Diastolic pressure <80 mmHg 0.058 >80 mmHg 0.043 0.020
C-reactive protein <5 mg/L 0.055 >5 mg/L 0.047 0.2 (NS)
Cholesterol/HDL < 4.5 0.059 >4.5 0.049 0.2 (NS)
TABLE III.—The average values of clinical tests for subjects with suf-
ficient and insufficient or deficient levels of vitamin D.
Serum 25-OH vitamin D levels
Clinical tests <40 ng/mL 40 ng/mL P for trend
VLDL 31.2 18.7 0.002
Systolic blood pressure 127 115.8 0.030
Diastolic blood pressure 76.6 66.4 0.003
Cholesterol/HDL ratio 3.7 3.0 0.020
Triglycerides 162 110 0.050
C-reactive protein 2.7 1.7 0.080
Vol. 52 - Suppl. 1 to No. 2 PANMINERVA MEDICA 5
which are similar to LDLs but can more easily pene-
trate the artery wall. Data of inverse correlation of risk
factors with EPCs are shown in Table II.
Data in Table II show the mean percentage of EPCs
for levels of risk factors higher and lower than the
upper border of the normal range and p-values for
trend. For all parameters except C reactive protein,
borderlines for risk factors are chosen as the highest
level of normal range (mean + 2SD) previously esti-
mated in our clinical laboratory. For CRP the level of
borderline equals 5 mg/L and marks the level of high
risk of cardiovascular disease. The average percentages
of EPCs for levels of risk factors higher and lower
than the highest level of normal range are presented in
Table II and show a significant difference in the level
of EPCs for the level of fasting glucose,VLDL, and
blood pressure.
Distributions of the percentage of endothelial prog-
enitor cells in groups of subjects with levels of glu-
cose, VLDL, and systolic pressure higher or lower
than upper borderline of normal range are presented
in Figure 2.
According to our data, there was an inverse corre-
lation between indicated levels of risk factors and the
number of endothelial progenitor cells in circulation,
and a trend towards a lower level of EPCs for subjects
with an increased level of fasting glucose,VLDL, and
blood pressure. For a VLDL level less than 30 mg/dL,
the average value for the percentage of EPCs in cir-
culation was 0.061%, and for VLDL higher than 30
mg/dL the mean value of EPCs was 0.035% (P<0.001).
The inverse association was also found between the
fasting level of glucose and the level of EPCs (0.060%
for the level of glucose less than 100 mg/dL, and
0.044% for the level of glucose higher than 100 mg/dL,
P<0.02). According to the linear correlation analysis,
there was statistically significant inverse correlation
between the level of EPCs and the level of glucose
(P<0.05) and VLDL (P<0.01).
The mean level of EPCs was decreased from 0.06%
for the levels of systolic pressure less than 140 mmHg
to 0.044% for systolic pressure greater than 140 mmHg
(P<0.01). Diastolic pressure mean values of EPCs
were decreased from 0.058% to 0.043% for borderline
pressure 80 mmHg (P<0.02). According to these
results, increased blood pressure was related to a
decreased number of endothelial progenitor cells, and
participants with increased blood pressure had the
reduced number of EPCs in circulation.
The comparison of the levels of C-reactive protein
with the measured level of EPCs for all participants
demonstrated that for a level of CRP higher than 5,
the mean number of endothelial progenitor cells was
decreased from 0.055% to 0.047%, but the difference
was not statistically significant.
Finally, there was an inverse association between
the levels of several risk factors and the EPC number,
and the percentage of circulating CD34+KDR+
endothelial progenitor cells was decreased with
increased values of blood tests, which are indicators of
the occurrence of cardiovascular events or diabetes.
Serum vitamin D inversely correlated with the level of
lipoproteins responsible for the increased cardio-
vascular risk and the level of blood pressure
Because vitamin D may play a role in blood pressure
regulation and vitamin D deficiency may alter the
effects of risk factors, we examined the association
between vitamin D status and cardiovascular risk fac-
tors. The values of cholesterol/HDL ratio, triglyc-
erides, very-low density lipoproteins, C-reactive pro-
tein, and blood pressure averaged for subjects with a
level of vitamin D higher and lower than 40ng/mL are
Distribution of EPCs for different levels
of glucose, VLDL and systolic pressure
<30 mg/dL
30 mg/dL
<100 mg/dL
100 mg/dL
<140 mg/dL
140 mg/dL
Figure 2.—Percentage of circulating EPCs in subjects with higher and
lower than high borderline of normal range levels of glucose,VLDL, and
systolic pressure.
presented in Table III. For a vitamin D level higher
than 40ng/mL, there was a decrease in diastolic pres-
sure (76.6 for vitamin D levels less than 40 ng/mL
and 66.4 for vitamin D levels higher than 40 ng/mL,
P<0.003). For systolic pressure, there was also a
decrease in values from 127 to 115.8 with P for trend
0.03 for subjects with a sufficient level of vitamin D in
comparison with subjects with an insufficient or defi-
cient level of vitamin D.
Vitamin D levels were inversely correlated with the
level of lipoproteins responsible for the increased car-
diovascular risk. There was an inverse relationship
between the levels of vitamin D and cholesterol to
HDL ratio. This factor is considered as a marker of
cardiovascular disease with the average risk factor in
the range between 3.4 and 5.0. Subjects with suffi-
cient vitamin D status (?40 ng/mL) showed reduction
of this parameter from average value 3.7 to 3.0
(P<0.02). Vitamin D deficiency was associated with
increased level of VLDL (31.2 mg/dL versus 18.7
mg/dL, P<0.002).
The increased level of CRP is considered a risk fac-
tor of cardiovascular disease. Mean values of CRP for
the ranges of vitamin D higher and lower than 40
ng/mL were 1.7 and 2.7 (P value for trend 0.08).
This study indicates that vitamin D status has an
effect on the number of EPCs in circulation and on
the ability of peripheral mononuclear cells to differ-
entiate in angiogenic cells. Mean values of EPCs for
subjects with a sufficient level of vitamin D (30-40
ng/mL) were higher than for subjects with an insuffi-
cient or deficient level of vitamin D (0.069 versus
0.045, P<0.01). The number of circulating angiogenic
cells developed from the peripheral mononuclear cells
was higher in subjects with a higher level of vitamin
D in the blood.
The possible explanation for these results may be that
the vitamin D hormone is a developmental hormone.
A higher level of vitamin D in circulation and genet-
ic variations in response to vitamin D may have an
impact on the ability of stem cells in circulation to
differentiate in endothelial phenotype. This possibil-
ity is supported by a study in which it was shown that
1,25(OH)2D3 may regulate phospholipase C produc-
tion by the cells, which in turn may modulate signal
transduction by receptors with tyrosine kinase activi-
ty, including VEGF-R1 and VEGF-R2 27 Another study
has shown that vitamin D has an effect on the prolif-
eration of stem cells (human bone-marrow derived
CD34+ and human peripheral blood-derived CD133+
cells).28 Our data of increased level of circulating EPCs
in subjects with a sufficient level of vitamin D may
be explained by the ability of vitamin D to modulate
the number of stem cells and differentiate these cells
in progenitor phenotype.27-29
An increased number of CACs in subjects with a
sufficient level of vitamin D may be explained by the
fact that during angiogenic cell development growth
factors presented in medium could modulate the
expression of the nuclear vitamin D receptors, pre-
sented in several subpopulations of mononuclear cells,
which will contribute to the development of angio-
genic types of cells.
Our study supported results of other studies that
demonstrated that risk factors of cardiovascular disease
and diabetes have an inverse correlation with the num-
ber of circulating EPCs.16, 17, 30 Cardiovascular risk
factors induce endothelial injury and a cascade of pro-
inflammatory events, resulting in the infiltration of
monocytic cells and smooth muscle cells prolifera-
tion, which leads to the formation of atherosclerotic
lesions. EPCs incorporate into the sites of neovascu-
larization and provide endothelial repair. However,
continued exposure to cardiovascular risk factors not
only damages the endothelial layer but may also lead
to depletion of EPCs.
In this study, we compared the levels of EPCs with
risk factors. Our data demonstrated that there is an
association between increased blood pressure and the
level of circulating EPCs. The percentage of EPCs
was decreased from 0.06 to 0.04 for populations with
a level of systolic pressure higher than 140 mmHg
(P<0.01). An increased level of diastolic pressure had
an inverse association with the number of EPCs (0.058
for diastolic pressure less that 80 mm Hg and 0.043 for
diastolic pressure higher than 80 mmHg, P<0.02). The
same tendency was found for the cholesterol/HDL
ratio, concentration of very-low density lipoproteins,
and increased level of fasting glucose. The mecha-
nism by which risk factors may affect EPCs has been
suggested in studies in which it was hypothesized that
progenitor cells are more sensitive to apoptosis induc-
tion.17, 31
The difference between two groups of subjects with
sufficient and insufficient or deficient levels of vitamin
Vol. 52 - Suppl. 1 to No. 2 PANMINERVA MEDICA 7
D was significant for cholesterol/HDL ratio, VLDL,
triglycerides, and blood pressure. A level of vitamin D
higher than borderline 40 ng/mL demonstrated a pos-
itive effect on blood pressure. While it is clear that
vitamin D plays some role in the regulation of blood
pressure, the mechanism of these complex relation-
ships must be evaluated.
Blood vessels and the heart have large numbers of
vitamin D receptors, which means that vitamin D is
providing some function in regulating these tissues.
Laboratory studies have found that vitamin D sup-
presses the activity of the hormone renin, high levels
of which can cause raised blood pressure.32
To maximize health and reduce the risk of common
diseases, it is important to pay attention to the 25(OH)D
concentrations. Maintaining a healthy 25(OH)D con-
centration may be important to prevent coronary dis-
ease. According to our results, the minimum concen-
tration of 25(OH)D should be 40 ng/mL; and for max-
imum bone health and prevention of many chronic
diseases, the vitamin D concentration should be high-
er than 40 ng/mL. Larger clinical trials evaluating
nutritional, environmental and population factors may
better define the possible roles of vitamin D levels in
cardiovascular prevention.
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... 131,132 A positive correlation between serum levels of vitamin D and circulating EPCs as well as cultured angiogenic cells suggests a possible role of vitamin D as a developmental hormone for stem cells that differentiate into the endothelial phenotype. 133,134 Study done by Mikirova et al., 135 indicated a positive correlation between serum level of vitamin D (25[OH]D) and circulating EPC as well as cultured angiogenic cells suggesting a possible role of vitamin D3 as a developmental hormone for stem cells which differentiates into endothelial phenotype. ...
... In the present study, we further clarified the role of the level of circulating EPCs in predicting all-cause and cardiovascular mortality in patients on maintenance hemodialysis. Vitamin D has the positive effect on the number of circulating EPC and optimal level of 25-vitamind D can reduce the risk of cardiovascular event and diabetes (26). Calcitriol, active form vitamin D3, stimulate endothelial colony-forming cells (ECFCs) proliferation through increasing VEGF expression and pro-MMP-2 activity in vitro, which is very important in angiogenesis (27). ...
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Background: The endothelial progenitor cells (EPCs) dysfunction is a critical event in the initiation of atherosclerotic plaque development and the level of circulating EPCs can be considered a biomarker of cardiovascular events. The level and functional change in EPCs has been investigated in hemodialysis patients, but the effect of absolute number of EPCs on risk of death has not yet been explored. We hypothesized that the number of EPCs predicted death from cardiovascular and all-cause mortality in hemodialysis patients. Methods: We evaluate the association between endothelial progenitor cells and clinical outcome in 154 patients on maintenance hemodialysis. The blood sample was drawn at the time of patient enrollment and EPCs were identified by flow cytometry using triple staining for CD34/CD133/KDR. Results: The median duration of follow-up was 4.19 years. There were 79 (51.3%) deaths during the follow-up period, 41 of whom died due to a confirmed cardiovascular cause. The cumulative survival was greater in the high-EPC group than the low-EPC group for all-cause and cardiovascular mortality. Decreased EPCs levels were associated with a significant increase in the risk of cardiovascular and all-cause mortality after adjusting for age, gender, current smokers, diabetes mellitus, and hypertension. Conclusions: The level of circulating EPCs independently predicts the clinical outcome in patients on maintenance hemodialysis. Thus, the EPCs levels may be a useful predictive tool for evaluating the risk of death in maintenance hemodialysis patients.
... Mikirova et al. found that vitamin D status has an effect on EPC number and on the ability of peripheral mononuclear cells to differentiate in angiogenic cells. In their study, mean values of EPCs for subjects with a sufficient level of vitamin D were higher than for subjects with an insufficient or deficient level of vitamin D. They suggest that a higher plasmatic level of vitamin D may have an impact on the ability of stem cells in circulation to differentiate in endothelial phenotype [100]. However, further studies are needed to explain the possible correlation between these "non-classic" CV risk factors and the EPCs. ...
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Objective. To identify, evaluate, and synthesize evidence on the predictive power of circulating endothelial progenitor cells (EPCs) in cardiovascular disease, through a systematic review of quantitative studies. Data Sources. MEDLINE was searched using keywords related to “endothelial progenitor cells” and “endothelium” and, for the different categories, respectively, “smoking”; “blood pressure”; “diabetes mellitus” or “insulin resistance”; “dyslipidemia”; “aging” or “elderly”; “angina pectoris” or “myocardial infarction”; “stroke” or “cerebrovascular disease”; “homocysteine”; “C-reactive protein”; “vitamin D”. Study Selection. Database hits were evaluated against explicit inclusion criteria. From 927 database hits, 43 quantitative studies were included. Data Syntheses. EPC count has been suggested for cardiovascular risk estimation in the clinical practice, since it is currently accepted that EPCs can work as proangiogenic support cells, maintaining their importance as regenerative/reparative potential, and also as prognostic markers. Conclusions. EPCs showed an important role in identifying cardiovascular risk conditions, and to suggest their evaluation as predictor of outcomes appears to be reasonable in different defined clinical settings. Due to their capability of proliferation, circulation, and the development of functional progeny, great interest has been directed to therapeutic use of progenitor cells in atherosclerotic diseases. This trial is registered with registration number: Prospero CRD42015023717.
... This suggests that vitamin D deficiency might contribute to depletion of EPCs and endothelial dysfunction in patients with type 2 diabetes. The association of vitamin D status with the level of circulating EPCs has been also shown in healthy adults, in whom EPCs (CD34+/KDR+ cells) and blood pressure regulation were positively associated with levels of 25-OH-D>40 ng/ml (166). The expression of 1-alpha-hydroxylase (CYP27B1) in human bones has been described. ...
... Few studies have evaluated the relation between EPC count and vitamin D status. Mikirova et al. [29] and Yiu et al. [17] have shown positive correlation between 25(OH)D levels and CD34þ/KDRþ and CD133þ/KDR þ EPC counts, respectively. Yiu et al. failed to demonstrate a beneficial effect of vitamin D replacement on EPC count in a type 2 diabetic population [21]. ...
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Background: Recent studies have revealed a relationship between vitamin D deficiency and atherosclerosis. This study aims to investigate the impact of vitamin D deficiency and replacement on markers of subclinical atherosclerosis in young premenopausal women in whom vitamin D deficiency is prevalent. Methods: Thirty-one premenopausal vitamin D deficient women and 27 age and gender-matched control subjects were enrolled in this study. Markers of subclinical atherosclerosis including carotid intima-media thickness (cIMT), flow-mediated dilatation (FMD), endothelial progenitor cell (EPC) count and cytokine levels were determined at baseline. All measurements were repeated at 6-month follow-up in vitamin D-deficient subjects after vitamin D replacement. Results: Vitamin D deficient premenopausal women had lower FMD (9.9 ± 1.3 vs. 13.8 ± 1.7%, p < 0.001) and EPC counts at baseline. This population also had lower IL-10 and higher IL-17 levels. A 6-month vitamin D replacement therapy resulted in a significant increase in FMD (9.9 ± 1.3 vs. 11.4 ± 1.4%, p < 0.001) and EPC counts. Furthermore, cytokine profile shifted toward a more anti-inflammatory phenotype including elevated IL-10 and decreased IL-17 levels. cIMT was not different between patient and control groups and did not change following vitamin D replacement. Change in 25(OH)D and IL-17 levels were independent predictors of the change in FMD measurements following vitamin D replacement. Conclusion: This study demonstrates that endothelial function is impaired in otherwise healthy vitamin D deficient young premenopausal women and improves with 6-month replacement therapy. Immune-modulatory effects of vitamin D may, at least partly, be responsible for its beneficial effects on vascular health. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
... Vitamin D deficiency has been associated with endothelial dysfunction in various cross sectional association studies. We have summarized the most recent studies which have shown an association with 25(OH)D concentrations (Table 1) [73][74][75][76][77][78][79][80][81][82][83][84]. In these studies, various methods have been used to measure endothelial function. ...
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Introduction and background Vitamin D deficiency has been associated with cardiovascular diseases (CVD) and its surrogate indicators such as endothelial dysfunction. It is an independent predictor of CVD and all-cause mortality. Methods We review the updated literature surrounding vitamin D and the endothelium spanning molecular, translational and clinical studies including randomized controlled trials (RCTs). We review the possible actions of vitamin D on the quiescent and activated endothelium including lessons from animal models. We review the recent literature for association of Vitamin D deficiency with endothelial dysfunction and cardiovascular complications, and for clinical trials done to look at the effect of vitamin D supplementation on the endothelium and cardiovascular outcome. Results and Conclusion Vitamin D deficiency is associated with endothelial dysfunction and cardiovascular diseases. Vitamin D stabilizes the quiescent endothelium, modulates certain stages of endothelial activation, and is involved in the repair of the damaged endothelium in vitro and in vivo. Twelve recent cross sectional studies, including 2086 subjects of varying ethnic groups, show an association between endothelial dysfunction and vitamin D deficiency. Yet 10 recent RCTs of vitamin D supplementation involving 824 subjects have failed to show significant improvements in endothelial function in the short term. So far, RCTs have not been able to confirm or refute the benefit of vitamin D supplementation on vascular mortality. Longer term randomized controlled trials using doses of vitamin D to optimize serum 25(OH)D concentrations to 20.0-40.0 ng/mL (50.0-100.0 nmol/L) or using vitamin D analogues with no calciotropic effects are needed to assess endothelial function and cardiovascular outcomes.
... The prevalence of insufficient vitamin D is higher in PCOS patients (53). Vitamin D dysregulation and deficiency is correlated with CVDs and affects EPCs (54,55). Therefore, administration of vitamin D may have beneficial effects on CVD risk factors in PCOS patients (56-58). ...
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Polycystic ovary syndrome (PCOS), the most common endocrine disorder affecting women of reproductive age, is characterized by hyperandrogenism and insulin resistance. Women with PCOS have a higher risk for cardiovascular diseases (CVDs) and endothelial dysfunction. The mechanisms underlying these risks are unclear. Human peripheral blood contains circulating endothelial progenitor cells (EPCs) derived from bone marrow that have the ability to proliferate and differentiate into mature endothelial cells, which may contribute to vessel homeostasis and repair. PCOS is associated with insulin resistance, hyperinsulinemia, and dyslipidemia, which may result in EPC dysfunction. In this review, we summarize the potential mechanisms of EPC dysfunction in PCOS, which possibly result in a higher genesis of CVDs in PCOS-affected subjects.
Background: Type 2 diabetes mellitus (T2DM), a chronic metabolic disorder caused by insulin resistance (IR) and elevated blood glucose level, may lead to endothelial dysfunction. This can result in the development of various vascular complications, even in clinically controlled glycemic state. Aim: It has been experimentally proven that cytokine influences both IR and endothelial progenitor cell (EPC) dysfunction in T2DM patients. The present study evaluated the effect of clinical and metabolic risk factors and cytokine levels on IR and EPC, which are used as critical early biomarkers for estimating the risks associated with T2DM. Methods: The study involved 58 T2DM patients. They were further subdivided into three groups based on IR score: 32 (55.17%) with normal, 11 (18.97%) with mild-moderate and 15 (25.86%) with severe IR. The relationship of clinical, metabolic and immune mediators with IR and EPCs was verified. Results: HbA1c% was significantly elevated in severe (P=0.022) and mild-moderate IR groups (P= 0.012) than the normal group. The IR normal group had significantly elevated TNF levels compared to mild-moderate and severe groups. The regression analysis indicated that patients with increased body mass index (BMI) were 19.5% more likely to be significantly associated with severe IR. Association studies demonstrated that IL6 and IL10 values correlated with EPCs. Conclusion: IL6 and IL10 were associated with circulating EPCs than IR and other clinical characteristics including glycemic control (glycated hemoglobin). TNF-α was associated with IR, but had no relationship with EPCs. The effect of cytokine status on IR and circulating EPCs in T2DM may indicate the risk of vascular complications.
Cardiovascular disease is the number one killer in the UK, causing more than 50 000 premature deaths per year, at a cost of over £30 billion to the economy (British Heart Foundation, 2010). Reducing this burden is a priority of the Government and health professionals (Department of Health, 2000). The aim of this paper is to inform and update nurses on four aspects. Firstly, to examine a more accurate test than cholesterol to predict cardiovascular risk that used C-reactive protein (CRP), an inflammatory marker, called the Reynold's Risk Score. Use of this score reclassified almost half of women, and one-fifth of men, into lower or higher risk categories, more accurately compared to conventional tools (Ridker et al, 2007; Ridker et al, 2008b). Secondly, to highlight a potential change to the indications for statin-therapy; an indication for those who ordinarily would not receive a statin: healthy middle-aged adults with normal or low cholesterol, but elevated CRP. This includes discussion of the JUPITER trial and its sub-analyses. This large, multicentre, double-blind randomized, placebo-controlled trial in apparently healthy men over the age of 50 years and women over 60 years, with normal or low cholesterol but elevated CRP, demonstrated significant benefit. Rosuvastatin 20 mg per day compared to a placebo reduced myocardial infarction and stroke by half, and reduced venous thromboembolism by almost half (Ridker et al, 2008a; Glynn et al. 2009; Everett, et al, 2010). Thirdly, to discuss the pleiotropic effects of statins, which include reduction of CRP (Ridker et al, 2008a), increases in endothelial repair cells (Spiel, et al, 2008), alteration of clotting factors (Glynn, et al, 2009), and enhancement of vitamin D metabolism (Yavuz et al, 2009). Fourthly, to discuss evidence that the pleiotropic effects of statins may be attributable to the vitamin D effect. This paper therefore evaluates the evidence suggesting that vitamin D supplementation may attain the same benefit as statins (Grimes, 2006), in addition to reducing statinassociated side-effects when co-administered (Ahmed et al, 2009).
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In a cross-sectional, population-based study we measured casual, seated blood pressure with a random-zero sphygmomanometer and 1,25-dihydroxyvitamin D (1,25-[OH]2D) with a protein-binding assay in 373 women aged 20-80 y. 1,25-(OH)2D, an active metabolite that regulates serum calcium, was associated significantly and positively with systolic blood pressure (p = 0.020) and diastolic blood pressure (p = 0.003) after adjustment for age, Quetelet's index (a measure of obesity), and current thiazide use. A model including age, Quetelet's index, current thiazide use, and 1,25-(OH)2D explained 37% of the variability in systolic blood pressure observations, of which 7% of variability was explained by 1,25-(OH)2D. In this geographically defined population of women, the variability of blood-pressure measurements attributable to 1,25-(OH)2D was of the same order of magnitude as that attributable to Quetelet's index.
Conference Paper
Vitamin D deficiency is now recognized as an epidemic in the United States. The major source of vitamin D for both children and adults is from sensible sun exposure. In the absence of sun exposure 1000 IU of cholecalciferol is required daily for both children and adults. Vitamin D deficiency causes poor mineralization of the Collagen matrix in young children's bones leading to growth retardation and bone deformities known as rickets. In adults, vitamin D deficiency induces secondary hyperparathyroidism, which causes a loss of matrix and minerals, thus increasing the risk of osteoporosis and fractures. In addition, the poor mineralization of newly laid down bone matrix in adult bone results in the painful bone disease of osteomalacia. Vitamin D deficiency causes muscle weakness, increasing the risk of falling and fractures. Vitamin D deficiency also has other serious consequences on overall health and well-being. There is mounting scientific evidence that implicates vitamin D deficiency with an increased risk of type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common deadly cancers. Vigilance of one's vitamin D status by the yearly measurement of 25-hydroxyvitamin D should be part of an annual physical examination.
Mouse myeloid leukemia cells can be induced to differentiate into macrophages in vitro by 1 alpha,25-dihydroxyvitamin D3, the active form of vitamin D3. The minimal concentration of 1 alpha,25-dihydroxyvitamin D3 to induce the cell differentiation was 0.12 nM. The degree of cell differentiation in various markers induced by 12 nM 1 alpha,25-dihydroxyvitamin D3 was nearly equivalent to that induced by 1 microM dexamethasone, the most potent known stimulator. Among several markers of the differentiation by 1 alpha,25-dihydroxyvitamin D3, phagocytic activity was induced within 24 hr, and this was followed by induction of lysozyme and locomotive activities. Similar changes were also induced by 0.01-1 microM 1 alpha-hydroxyvitamin D3. 25-Hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3 showed only weak inducing activity. These results suggest the possibility that, in addition to its wellknown biological activities in enhancing intestinal calcium transport and bone mineral mobilization, 1 alpha, 25-dihydroxyvitamin D3 is involved in the differentiation of bone marrow cells.
Previous studies have shown that 1,25-(OH)2D3 stimulates phospholipase A2 (PA2) activity in growth zone chondrocytes (GC), but has no effect on the resting zone chondrocyte (RC) enzyme activity. 24,25-(OH)2D3 inhibits the RC enzyme but has no effect on the GC. This study examined whether the vitamin D metabolites affect arachidonic acid turnover in their contra-target cell populations. Incorporation and release of [14C]arachidonate was measured at various times following addition of hormone. Acylation and reacylation were measured independently by incubating with p-chloromercuribenzoate. The results demonstrated that 1,25-(OH)2D3 has no effect on arachidonic acid turnover in RC, but stimulates turnover in GC. In contrast, 24,25-(OH)2D3 stimulates arachidonic acid turnover in RC, but inhibits both incorporation and release in GC. To determine whether direct interaction with PA2 is one mechanism by which 1,25-(OH)2D3 and 24,25-(OH)2D3 regulate arachidonic acid release, snake venom (Niger niger) PA2 was incubated with the vitamin D metabolites. Enzyme specific activity was inhibited by 24,25-(OH)2D3 and stimulated by 1,25-(OH)2D3 in a time- and dose-dependent manner. These results suggest that at least part of the direct effect of vitamin D3 metabolites on cell membranes may be related to changes in PA2 activity. The regulation is related to the stage of differentiation of the target cell population. Changes in fatty acid acylation and reacylation may be one mode of vitamin D3 action in cartilage.
Renin secretion by the kidney is inhibited by an increase in free intracellular calcium concentration. This increase in free intracellular calcium content may be augmented by serum 1,25-dihydroxyvitamin D. In 10 subjects with high renin hypertension, an increase in dietary sodium intake resulted in an increase in urinary calcium excretion (2.5 to 3.4 mmol/L, P = .011) and an increase in serum 1,25-dihydroxyvitamin D (51.2 to 61.0 pmol/L, P = .045). An inverse correlation existed between the change in vitamin D and the change in plasma renin activity (r = -0.765, P = .01). An inverse correlation also existed between the change in plasma renin activity and the change in mean arterial blood pressure (r = -0.757, P = .011). It is postulated that the increase in dietary sodium led to an increase in serum 1,25-dihydroxyvitamin D concentration, which may have contributed to an increase in intracellular calcium concentration, a decrease in renal secretion of renin, and a fall in plasma renin activity. The resultant fall in PRA in part effected the change in blood pressure to the increased sodium intake. Therefore, 1,25-dihydroxyvitamin D may be a mediator in the response of high renin hypertension to increased sodium intake.
Blood samples taken in 1974 in Washington County, Maryland, from 25 620 volunteers were used to investigate the relation of serum 25-hydroxyvitamin D (25-OHD) with subsequent risk of getting colon cancer. 34 cases of colon cancer diagnosed between August, 1975, and January, 1983, were matched to 67 controls by age, race, sex, and month blood was taken. Risk of colon cancer was reduced by 75% in the third quintile (27-32 ng/ml) and by 80% in the fourth quintile (33-41 ng/ml) of serum 25-OHD. Risk of getting colon cancer decreased three-fold in people with a serum 25-OHD concentration of 20 ng/ml or more. The results are consistent with a protective effect of serum 25-OHD on colon cancer.
To determine whether the changes in cardiovascular function that accompany vitamin D3 deficiency are the direct result of hypovitaminosis D3 or a response to the hypocalcemia that accompanies vitamin D3 deficiency, rats were maintained for 9 wk on a vitamin D3-deficient diet containing either low (0.4%) calcium or high (2.5%) calcium to prevent hypocalcemia. Rats were also maintained on the low-calcium, vitamin D3-deficient diet for 9 wk and then transferred to diets designed to reverse hypocalcemia or vitamin D3 deficiency. The results demonstrate that the changes in in vitro cardiac contractile function that accompany vitamin D3 deficiency 1) could not be prevented by preventing the hypocalcemia that normally accompanies vitamin D3 depletion or 2) could not be reversed by restoration of serum calcium to normal levels after the initial period of vitamin D3 depletion. In contrast, the change in in vitro vascular muscle contractile function observed in vitamin D3-deficient, hypocalcemic rats could be prevented by maintaining serum calcium at normal levels and also reversed by restoration of serum calcium to normal after an initial period of vitamin D3 deficiency. These observations indicate that hypocalcemia does not account for the changes in cardiac contractile function that result from vitamin D3 depletion and suggest a direct role for vitamin D3 or its metabolite 1,25-dihydroxyvitamin D3 in regulating cardiac contractility. Possible mechanisms underlying this direct effect were also explored.
In our previous studies, perifused islets from vitamin D-deficient (D-def) rats showed marked impairment of glucose-induced biphasic release, accounted for at least in part by a decrease in food intake. In studies reported here, we test whether D-def rat islets have an impaired response to 5.6 mM glucose or tolbutamide, (T), and if so, whether this impairment is related to a decrease in food intake or a defect in islet calcium metabolism. We isolated islets of normal rats, D-def rats, and rats pair fed (PF) to D-def rats. Biphasic insulin release from perifused islets and net 45Ca retention in lot-incubated islets were measured in response to 5.6 mM glucose, 0.37 mM T, or both. Compared with secretion from normal islets, biphasic insulin release from islets of both D-def rats and PF rats was diminished by greater than 50% in response to 5.6 mM glucose alone or 5.6 mM glucose plus T. Insulin secretion was not significantly different between islets of D-def rats and islets of PF rats. In contrast, net calcium retention in islets of D-def rats was decreased to 68% of retention in islets of PF rats. However, net calcium retention in islets of both PF and D-def rats increased in response to T. The pair-feeding experiments suggest that the decrease in insulin release from islets of D-def rats is due to the decrease in food intake associated with the D-def state.(ABSTRACT TRUNCATED AT 250 WORDS)