Current Protein and Peptide Science
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Current Protein and Peptide Science, 2019, 20, 984-995
Vitamin D and Vitamin D Receptor: New Insights in the Treatment of
Lin Lin1, Lei Zhang1, Chao Li1, Zhibo Gai1,* and Yunlun Li1,*
1Shandong University of Traditional Chinese Medicine, 250003 Ji-nan, China
A R T I C L E H I S T O R Y
Received: September 28, 2 018
Revis ed: April 29 , 2019
Accepted: June 01 , 2019
Abstract: Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis.
But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflam-
mation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distrib-
uted in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin
D and VDR in hypertension has received extensive attention. Hypertension is a disease with high inci-
dence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have
shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting
renin-angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vas-
cular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with in-
creased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly
raise BP and promote target organ damage. Due to the high correlation between vitamin D and hyper-
tension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The
aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and
protecting against the target organ damage.
Keywords: Vitamin D, vitamin D receptor, hypertension, hypertensive organ damage, therapeutic targets, cardiovascular risk.
The classic function of vitamin D is to promote the intes-
tinal absorption of calcium and maintain skeletal health. In
recent decades, we have found vitamin D receptor (VDR)
exists in almost all human cells and modulates about 3 per-
cent of human genes by activating a specific transcription
program . So more and more attention has been paid to
the role of vitamin D in non-skeletal d iseases, including dia-
betes mellitus, autoimmune disease, cancer and cardiovascu-
lar disease (CVD). It has been showed that vitamin D status
is inversely correlated with higher disease frequency and
disease severity , as well as vitamin D deficiency is an
independent risk factor of total mortality .
Hypertension is a global public health problem, charac-
terized by high morbidity, high mortality and a mass of com-
plications. World Health Organization reported that one in
three adults worldwide has raised blood pressure (BP), which
causes approximately half of all deaths from heart disease
and stroke. The risk factors of hypertension mainly involve
in obesity, mental stress, high salt diet and so on, meanwhile
there is growing evidence that vitamin D deficiency is asso-
ciated with hypertension and the increased risk of CVD. A
prospective analysis showed that people with low vitamin D
*Address correspondence to these authors at the Shandong University of
Traditional Chinese Medicine, 250003, Ji-nan, China;
Tel: +86-0531-68616038; E-mails: firstname.lastname@example.org (Y.L.);
concentrations were three times more likely to have hyper-
tension than those with high vitamin D concentrations . In
hypertension patients, low serum vitamin D levels increase
the risk of CVD by 60% . VDR activation regulates the
activity of the renin-angiotensin-aldosterone system
(RAAS), recovers endothelial function, suppresses inflam-
mation and immune system, all crucial mediators of hyper-
tension and target organ damage. Hence, in this review, we
will summarize the mechanisms of the vitamin D and VDR
in regulating BP, and in addition, gather epidemiologic and
clinical evidence to evaluate the protective effect of vitamin
D and VDR on hypertension.
2. PHYSIOLOGY OF VITAMIN D AND VDR
Vitamin D is a group of fat-soluble molecules, and the
most important of which are vitamin D2 (ergocalciferol) and
vitamin D3 (cholecalciferol). A large amount of vitamin D is
converted as vitamin D3 from 7-dehydrocholesterol after
exposure to ultraviolet-B (UVB) in the skin. Furthermore,
just 10-20% of vitamin D comes from the diet as vitamin D2
or vitamin D3 . Foods rich in vitamin D are mainly cod
liver oil, fish, animal liver, eggs and fortified milk. Also,
some fruits and vegetables are rich in vitamin D, such as
cherry, guava, persimmon, strawberry, red pepper, yellow
pepper, the chin flowers and so on. As natural traditional
Chinese medicine, calculus bovis and Yolk are often used to
treat osteoporosis and chondropathy.
1875-5550/19$58.00+.00 © 2019 Bentham Science Publishers
Regulation of Vitamin D and VDR in Hypertension Current Protein and Peptide Science, 2019, Vol. 20, No. 10 985
After vitamin D enters the body, it is hydroxylated in the
liver to 25-hydroxyvitamin D [25(OH)D, calcidiol], which is
the major circulating form of vitamin D and is accepted to
determine the overall vitamin D status . 25(OH)D is con-
verted by 1α-hydroxylase in the kidney to its bioactive form,
1,25-dihydroxyvitamin D [1,25(OH)2D, calcitriol], which
has much stronger specificity with VDR and is responsible
for most of vitamin D metabolic actions . Although only
the renal 1α-hydroxylase has a significantly promoting effect
to circulating 1,25(OH)2D levels, extrarenal 1α-hydroxylase
is also able to convert 25(OH)D to 1,25(OH)2D. Many other
cell types, such as vascular endothelial cells (EC) and vascu-
lar smooth muscle cells (VSMC), can express 1α -
hydroxylase with subsequent conversion of 25(OH)D to the
local production of 1,25(OH)2D . This local production
and breakdown is not subject to the same feedback controls
as renal production , but is significant to the non-skeletal
actions of vitamin D (Fig. 1) . The local production is one
of the reasons why the 25(OH)D is more clinically useful for
accessing vitamin D status than 1,25(OH)2D, and the others
include that the half-life of 25(OH)D is much longer(3 weeks
versus 8 hours) and the circulating concentration is 1000×
higher than 1,25(OH)2D .
VDR as a nucleophilic protein, is a biomolecule to medi-
ate 1,25(OH)2D biological effect. In addition to the tradi-
tional vitamin D target organs associated with calcium me-
tabolism, such as intestine, kidney, bone and parathyroid
glands, VDR also exists in the hair follicle, adipose tissue,
cancer cells, the blood lymphatic system, urogenital system
and nervous system [11, 12]. Furthermore, VDRs have been
found in all the major cardiovascular cell types including
cardiomyocytes [13-15], arterial wall cells [16, 17], and im-
mune cells [18, 19]. This suggests that vitamin D is also in-
volved in cellular functions unrelated to calcium metabolism.
VDR is divided into two categories: nuclear vitamin D
receptor (nVDR) and membrane vitamin D receptor
(mVDR). The mediation of VDR is mainly performed by
nVDR, but mVDR may be able to bind different ligands [20,
21]. In the absence of ligands, nVDR is used with cosuppres-
sor to bind to the vitamin D response elements (VDREs) of
target DNA and inhibit gene transcription. When circulating
1,25(OH)2D binds to the nVDR specifically in the nucleus,
nVDR then undergo phosphorylation and conformational
change, thus dissociating from cosuppressor. Activated
nVDR heterodimerizes with the retinoic x receptor (RXR)
and then the 1,25(OH)2D-VDR-RXR complex identifies and
binds to VDREs on DNA to regulate the expression of genes
under the function of transcription factors. Therefore, by
controlling the activation of nVDR, vitamin D affects auto-
immunity, tissue inflammation and cellular activity including
cell proliferation, differentiation, apoptosis and angiogenesis
[7, 22]. In addition to generate genomic responses in the tar-
get cells through nVDR, 1,25(OH)2D can interact with th e
mVDR that localized in cav eolae of the plasma membrane to
generate rapid nongenomic responses, which requires only a
few seconds to a few minutes [12, 23]. The rapid nonge-
Fig. (1). The process of vitamin D synthesis and metabolism. 80-90% vitamin D is transformed from 7-dehydrocholesterol in the skin.
Only a small fraction comes from diet, such as fish oil, eggs, fortified milk, etc. And then vitamin D is converted to 25(OH)D and
1,25(OH)2D, which are the major circulating form and bioactive form of vitamin D, respectively. Some extrarenal tissues or cells also ex-
press 1α-hydroxylase and produce local 1,25(OH)2D, which influences the inflammation, some cellular activity and cardiovascular health by
combining with lo cal VDR. While, the circulating 1,25(OH)2D in serum mainly regulates skeletal function.
986 Current Protein and Peptide Science, 2019, Vol. 20, No. 10 Lin et al.
nomic responses involve the rapid intestinal absorption of
Ca2+, secretion of insulin by pancreatic β -cells, opening of
voltage-gated Ca2+ and Cl- channels in osteoblasts, the rapid
migration of EC, stimulates lipogenesis and inhibits lipolysis
3. VITAMIN D DEFICIENCY AND HYPERTENSION
3.1. Definition and Risk Factors of Vitamin D Deficiency
It is estimated that about half the world’s total population
have low levels of vitamin D . The vitamin D status is
evaluated by the serum 25(OH)D level because of its higher
stability and concentration than 1,25(OH)2D. The definition
of vitamin D deficiency has been controversial. Most guide-
lines and diagnostic criteria agree that vitamin D deficiency
is defined as serum 25(OH)D level below 20 ng/mL (50
nmol/L), and insufficiency is between 20-30 ng/mL (50-75
nmol/L) [27-30]. The North American Institute of Medicine
defines vitamin D deficiency as serum 25(OH)D level below
12 ng/mL (30 nmol/L) . In the first international confer-
ence on controversies in vitamin D, 25(OH)D concentrations
below 12 ng/mL (30 nmol/L) was considered to increase risk
of rickets and osteomalacia, while 25(OH)D concentrations
between 20-50 ng/mL (50-125 nmol/L) seem to be sufficient
in the general population for skeletal health .
The risk factors of vitamin D deficiency involve in in-
adequate exposure to sunlight, season, latitude, time of day,
race, sex, skin pigmentation, sunscreen use, aging, obesity,
and sedentary lifestyle, as well as others. [27, 33] Sunlight is
essential for vitamin D synthesis. The researchers found that
mean 25(OH)D concentration was lower in blood samples
collected in winter/spring than in those collected in sum-
mer/fall . Moreover, compared with other races, black
participants have the lowest vitamin D levels . The rea-
son is that people with black skin absorb more UVB in the
melanin, therefore, require more sun exposure to produce
same amounts of vitamin D. Gender also has an impact on
vitamin D status. Female gender is independently associated
with severe vitamin D deficiency, and hypovitaminosis D is
associated with more aggressive coronary atherosclerosis in
women but not in men . What’s more, it has been shown
that percentage of body fat was closely related to vitamin D
deficiency . A survey showed that 76% of obese children
had insufficient vitamin D . And Blum et al. found that
vitamin D concentration in serum was significantly lower
than in subcutaneous fat tissue . This is because adipose
tissue contains VDR so that vitamin D is stored in adipose
tissue, which leads to the reduced bioavailability .
3.2. Cro ss-sectional and Epidemiologic Studies
Vitamin D deficiency is highly prevalent all over the
world, especially in the Middle-East and Asia . Although
people far from the equator are more likely to suffer from
vitamin D deficiency, the prevalence is not low in areas with
low latitudes and abundant sunshine [42, 43]. In a large sim-
ple Middle Eastern study of 60,979 patients from 136 coun-
tries with yearlong sunlight, 82.5% of subjects suffer vitamin
D insufficiency . Serum vitamin D levels vary widely
among ethnic groups. A survey about vitamin D levels in a
multiethnic Asian population showed that the 25(OH)D con-
centration of 76.1% participants is below 30 ng/mL. Com-
pared to Chinese ethnicity, Malay and Indian ethnicities are
closely related to suboptimal 25(OH)D concentration .
The proportion of persons with 25(OH)D＜40 nmol/L is 14-
18% in whole US population, while the ratio is up to 46-60%
in non-Hispanic blacks and reduced to 6-10% in non-
Hispanic whites .
Moreover, a large number of studies have shown a link
between vitamin D and hypertension. Anderson et al. found
a high prevalence of vitamin D deficiency in the general
healthcare population and a significant association between
low vitamin D levels and the increased risk of hypertension
. Similar results were found in pregnant women . A
retrospective cross-sectional study of overweight and obese
youth showed 45% subjects were 25(OH)D deficient. What’s
more, lower 25(OH)D levels were associated with the in-
creased systolic BP (SBP) and diastolic BP (DBP) .
Vishnu et al. found that SBP decreased by 0.19 mm Hg
among US adults for every 10 nmol/L increase in vitamin D.
The association between the higher vitamin D and lower
SBP differs according to ethnicity and gender. After
race/ethnic and gender stratification, only non-Hispanic
white females and non-Hispanic black females reflect this
association . A Mendelian randomization analysis testi-
fied higher 25(OH)D concentration was correlated with de-
creased BP and reduced odds of hypertension. The results
showed that each 10% increase in genetically instrumented
25(OH)D concentration caused a change of -0.37 mm Hg in
SBP, a change of -0.29 mm Hg in DBP and an 8.1% de-
creased odds of hypertension . A meta-analysis found the
pooled odds ratio of hypertension was 0.73 for the highest
compared with the lowest category of 25(OH)D concentra-
In hypertension patients, vitamin D deficiency is more
common. Zhang et al. showed that in hypertension patients
residing in Xinjiang of China, the mean 25(OH)D concentra-
tion was only 12.3 ng/mL and the prevalence of vitamin D
deficiency (<20 ng/mL) and insufficiency (20-30 ng/mL)
was 87.0% and 10.3%, respectively . Pöss et al. reported
low vitamin D states was associated with a decreased SBP
response in patients with resistant hypertension . In addi-
tion, vitamin D concentration was lower in p atients with
nondipper hypertension than those with dipper hypertension
3.3. Prospective Studies
Some prospective studies have indicated that lower
25(OH)D levels can independently predict clinically differ-
ence in the odds of subsequently developing hypertension. In
two prospective cohort studies, during 4 years of follow-up,
the risk of incident hypertension in men and women whose
measured plasma 25(OH)D levels below 15ng/mL is 6.13
and 2.67 times, respectively, compared to those with suffi-
cient 25(OH)D . Young women participating in the
Nurses’ Health Study 2 in lowest quartile of plasma
25(OH)D had 1.66 fold increased risk of developing incident
hypertension compared with subjects in the highest quartile
. Among 1,211 male physicians free of hypertension at
baseline, 695 developed hypertension over a mean of 15.2
years follow-up period. Men with lower concentration of
baseline plasma 25(OH)D had a higher risk of developing
Regulation of Vitamin D and VDR in Hypertension Current Protein and Peptide Science, 2019, Vol. 20, No. 10 987
4. MECHANISTIC LINKS BETWEEN VITAMIN D
4.1. Inhibition Activity of the Renin-angiotensin-
The RAAS is not only a circulating but a local tissue
hormone system, whose all components have been found in
cardiovascular organs [57, 58]. The main actions of the
RAAS is to regulate the BP and fluid and electrolyte homeo-
stasis . Recently, increasing evidence has manifested that
vitamin D maybe a negative endocrine regulator of the
RASS. Disruption of vitamin D signaling in VDR-/- or
1α(OH)ase-/- [VDR or 1α(OH)ase knockout] mice leads to
hyperreninemia, high BP and cardiac hypertrophy, while
1,25(OH)2D downregulates renin gene expression through a
VDR-dependent, and calcium- and PTH (parathyroid hor-
mone)-independent mechanism, suggesting that vitamin D
has a direct impact on the renin biosynthesis, BP homeosta-
sis and even the regulation of cardiac functions [59-63].
Even in wild-type mice, restraint of 1,25(OH)2D synthesis
also led to an increase in renin gene expression, whereas
1,25(OH)2D injection resulted in renin suppression . Vi-
tamin D affects not only circulating but local tissue RAAS.
Islet RAAS components have a growth trend in VDR-/- mice,
and calcitriol can normalize production of RAAS compo-
nents under high-glucose conditions . Moreover, it has
been confirmed that a number of vitamin D analogs have
ability to inhibit renin expression [65, 66]. As the cyclic
adenosine monophosphate (cAMP)-dependent protein kinase
A signaling pathway is a major regulatory pathway related
with renin production, one of the molecular mechanisms by
which 1,25(OH)2D suppresses renin gene transcription is to
block the activity of the cAMP response element .
The relationship between vitamin D and RAAS has also
been studied in clinical trials. Nearly 30 years ago, Burgess
showed an inverse relationship between 1,25(OH)2D and
plasma renin activity (PRA) in high renin essential hyperten-
sion . Over the years, a series of clinical trials have been
carried out, but the results are mixed. A study found that in
the group with vitamin D deficiency, PRA is correlated with
high BP and impaired structural and functional state of myo-
cardium. While, the individuals with optimal level of vitamin
D don’t have these correlation . In essential hypertensive
patients with hypovitaminosis D under constant salt intake
and free from drugs which interfere with RAAS, chronic
VDR stimulation doesn’t decrease BP directly but blunts
systemic RAAS activity, including plasma renin, aldoster-
one, PRA and Ang Ⅱ . In a randomized placebo-
controlled trial, vitamin D supplementation can reduce
plasma aldosterone concentration in patients with arterial
hypertension and 25(OH)D insufficiency, but no effect was
seen for plasma renin concentration or aldosterone to renin
ratio . A positive association between 25(OH)D and the
tissue sensitivity to Ang II in obese hypertensives had been
examined, as tissue sensitivity to Ang II is inversely related
to RAAS activity, suggesting that 25(OH)D deficiency may
enhance tissue RAAS activity in obesity . Though some
studies found that vitamin D had no effect on RAAS activity
[73-75], most of the vivo or vitro experiments have observed
that vitamin D and its analogs suppress the activity of circu-
lating or local RAAS to regulate BP.
4.2. Regulate Function of Endothelium and Vessel Wall
Vascular endothelium is a marker of cardiovascular
health, meanwhile, endothelial dysfunction leads to vaso-
spastic contractions and consequently, elevates BP. In 1990,
it has shown that administration of 1,25(OH)2D will increase
contractile force-generating capacity of resistance arteries by
a direct action on the vascular wall . The direct effect is
the result of VDR being widely distributed in vascular wall
Acute doses of vitamin D to healthy individuals will in-
crease vascular tone and reduce blood flow to tissue during
stressors . A cross-sectional study involved 852 subjects
demonstrated vitamin D and endothelium-independent vaso-
dilation are positively correlated in older women . An-
other found AChmax and percentage change of ACh response
were both lower in the vitamin D deficient group compared
with the nondeficient group, indicating low vitamin D levels
decreased microvascular endothelial-dependent vasodilata-
tion . Furthermore, parental vitamin D deficiency is also
associated with elevated BP levels in th e offspring, which is
caused by lower gene expression in the Panx1 promoter re-
gion and impaired endothelial relaxation in the large vessels
. Vitamin D insufficient was associated with flow-
mediated dilation (FMD) and carotid intima-media thickness
(IMT), which are the indicators of endothelial function and
preclinical atherosclerotic changes in the vascular, respec-
tively . Among individuals in the absence of clinical
disease, serum 25(OH)D is also significantly related to endo-
thelial functions and ventricular and arterial stiffness, re-
flected in the lower reactive hyperemia index [82, 83] and
higher pulse wave velocity with low vitamin D levels .
Cholecalciferol therapy to hypertensive or chronic kidney
disease patients with hypovitaminosis D resulted in the in-
creased brachial artery FMD , as well as the decreased
endothelial dysfunction biomarkers concentrations . A
recent meta-analysis also found a significant increasement in
FMD following vitamin D supplementation, indicating the
protective effect of vitamin D to endothelial function .
A large amount of experiments explained the protective
effect of vitamin D on vascular wall at the cellular and mo-
lecular levels. Vitamin D3 can affect endothelial activation in
the context of cytokine-induced destabilization and inhibit
the destabilizing effects on cell-cell junctions. Importantly,
the barrier-enhancing function of vitamin D3 is not only pre-
sent in its active metabolite- 1,25(OH)2D, but also in the
“inactive” dietary and mono-hydroxylated forms of the vita-
min D as well . Meanwhile, paricalcitol, a VDR activator
(VDRA), restored endothelial integrity, endothelial barrier
function and improved the cell-cell contact by increasing
vascular endothelial-cadherin at intercellular junctions .
Once activated by vitamin D, VDR can phosphorylate p38,
AKT and ERK to activate endothelial nitric oxide synthase
(eNOS) . Meanwhile, Andrukhova et al. have proved the
effect of vitamin D as a direct transcriptional regulator of
eNOS . eNOS is the key nitric oxide (NO) synthesizing
enzyme, and the reduced expression of eNOS in VDR mu-
tant mice led to endothelial dysfunction and increased arte-
rial stiffness . Similarly, through creating a model of
endothelial-specific VDR-/- mice, it has showed that vitamin
D and VDR modulated blood vessel relaxation and arterial
988 Current Protein and Peptide Science, 2019, Vol. 20, No. 10 Lin et al.
BP by regulating eNOS expression and phospho-vasodilator-
stimulated phosphoprotein levels . Furthermore, vitamin
D could facilitate angiogenesis in EC by increasing VEGF
expression and pro-matrix metalloproteinases (MMP)-2 ac-
tivity . Wong et al. found that 1,25(OH)2D decreases
endothelium-dependent contractions in the aorta of the spon-
taneously hypertensive rat (SHR) by reducing calcium influx
into the EC and suppressing the production of endothelium-
derived contracting factors . Zoccali et al. found serum
phosphate has a bearing on the beneficial effect of paricalci-
tol on endothelial function, indicating the endothelium pro-
tective effect by VDRA may be potentiated by controlling
phosphate at lower levels .
4.3. Reduce Vascular Oxidative Stress and Inflammation
Reactive Oxidative Species (ROS) are important intracel-
lular signals for vascular cells growth. Oxidative stress, a
state of ROS being excessive activated, is associated with
vascular diseases, such as hypertension and atherosclerosis.
Oxidative stress suppresses VDR expression in EC, which
could be prevented by 1,25(OH)2D . In an Ang Ⅱ cellular
model of hypertension, vitamin D improved endothelial
function by increasing bioavailable NO, reversing the imbal-
ance between NO and peroxynitrite (ONOO-) concentrations,
as well as reducing oxidative and nitroxidative stress .
Calcitriol can reduce oxidative stress by regulating transcrip-
tion of the radical generating and scavenging enzymes in-
stead of scavenging radical directly. Calcitriol improved the
impaired endothelium-dependent relaxations in renal arteries
by preventing ROS over-production and regulating a series
of oxidative stress-related proteins and superoxide dismu-
tase. The results were substantiated in hypertensive patients,
normotensive patients and SHR whatever in vivo or vitro
. Cholecalciferol effectively decreased liver oxidative
stress index and improved serum total antioxidant capacity,
thus suppressing oxidative stress-mediated vascular compli-
cations . Valcheva et al. have indicated that VDR
knockout in mice increased local production of Ang II in the
vascular wall, which is a mediator of oxidative stress,
prompting premature senescence. Vitamin D prevented
VSMC premature senescence by suppressing the local pro-
duction of Ang II and downstream free radicals .
Inflammation plays a negative role in endothelial func-
tion and vascular remodeling of hypertension patients. Pari-
calcitol and calcitriol suppressed the expression of inflamma-
tory markers, involved in IL-6, IL-8 and NF-κB [101, 102].
Calcitriol blunted the advanced glycation end products
(AGEs) -induced elevation of NF-κB-p65 DNA binding ac-
tivity to neutralize the deleterious actions of AGEs on EC
activities . Tumor necrosis factor-α (TNF-α) is a pro-
inflammatory cytokine, promoting endothelial dysfunction
with subsequent arterial stiffness. TNF-α increased tissue
factor (TF) expression and procoagulant activity in VSMC,
which can be blunted by vitamin D to inhibit the inflamma-
tion-induced thrombotic state . Ohsawa et al. also
found that 1,25(OH)2D and its potent analogs have antico-
agulant effects in monocytic cells by downregulating TF
expression, upregulating thrombomodulin (TM) expression
and counteracting the effects of TNF and oxidized low den-
sity lipoprotein (oxLDL) . Atherosclerotic plaque in the
aorta of ApoE-deficient mice can be prevented by paricalci-
tol and enalapril, due to the amelioration of inflammatory
and oxidative aortic injury. What’ more, the therapy that
paricalcitol combin ed with enalapril affords greater protec-
tion against atherosclerosis than either drug alone .
4.4. Improve Insulin Sensitivity
Insulin contributes to regulation of vascular function and
vasomotor balance. Insulin resistance, an independent risk
factor for primary hypertension, is a pathophysiological re-
sponse of tissue cells to the decrease of insulin sensitivity
and/or reactivity. Some studies have found that insulin resis-
tance and insulin sensitivity are closely associated with BP
and hypertension [107-109]. According to data, increased
insulin sensitivity by one unit reduced the risk of hyperten-
sion by 10% . The correlation between insulin sensitiv-
ity and vascular dilatory function has also been proven .
Furthermore, Daniel et al. found that acute hyperinsulinemia
caused by insulin resistance can significantly blunt or delay
renal sodium excretion in hypertensive patients .
Meanwhile, hyperinsulinemia is relevant with arterial stiff-
ness . Insulin resistance destroys glucose and lipid me-
tabolism [113, 114], causes endothelial dysfunction and acti-
vates the RAAS , which all lead to atherosclerosis and
ultimately hypertension. The evidences suggest that improv-
ing insulin sensitivity is an important measure to control BP
and improve vascular injury.
Low vitamin D levels is associated with insulin resis-
tance . Vitamin D deficiency contributes to the morbid-
ities of diabetes mellitus and hypertension in obese children
and adolescents . A recently study found that vitamin D
deficiency enhanced postprandial insulin concentrations and
homeostatic model assessment insulin resistance values in
female rats. Moreover, the deficiency of vitamin D reduced
sensitivity of the coronary arterio lar wall to insulin, which is
a common cause of the diminished coronary arteriole relaxa-
tion . Increased scavenger receptor expression is con-
sidered as a connection between diabetes and atherosclerosis.
Through suppression of macrophage endoplasmic reticulum
stress and c-Jun N-terminal kinase activation, 1,25(OH)2D
and VDR decreased the expression of scavenger receptors,
improved insulin signaling and restrained oxLDL and acety-
lated LDL (AcLDL)-derived macrophage cholesterol uptake
to prevent foam-cell formation and atherosclerosis .
5. VITAMIN D AND HYPERTENSIVE ORGAN DAM-
Severe hypertension always causes damage to blood ves-
sels, heart, kidney, brain and other organs. Vitamin D defi-
ciency may aggravate hypertensive organ damage. Several
studies have found that patients with low vitamin D level
increased risk of CVD and its mortality [119-122]. Vitamin
D has a potential benefit in lowering some of cardiovascular
risk markers including BP, total cholesterol, low density
lipoprotein cholesterol, glycated hemoglobin level and arte-
rial stiffness [123-125]. Compared with standard chow, the
double-transgenic rats (dTGR) received vitamin D-depleted
chow for 3 weeks exerted higher SBP, serum creatinine con-
centrations, atrial natriuretic peptide (ANP), brain natriuretic
peptide (BNP) and increased relative heart weights, reflect-
Regulation of Vitamin D and VDR in Hypertension Current Protein and Peptide Science, 2019, Vol. 20, No. 10 989
ing the injury of heart and kidney . Vitamin D defi-
ciency is associated with increased mean pulmonary artery
pressure, increased pulmonary vascular resistance and de-
creased cardiac output in pulmonary hypertension (PH) pa-
tients. While supplying PH rats with vitamin D improved
survival through suppressing right ventricular hypertrophy
. Vitamin D mediated RAAS inhibition and Klotho
expression to achieve a renal protective effects, referring to
depression of proinflammatory, profibrotic, and increased
antioxidative mediators in the kidney tissue . Moreover,
calcitriol improved kidney fibrosis by attenuating vascular
remodeling and ischemia, which are associated with in-
creased expression of endothelin-1, ETBR and eNOS .
Hypertension always damages arteries, causing small ar-
tery spasm and vascular wall remodeling, while lumen steno-
sis in turn promo tes the maintenance and development of
hypertension. Vitamin D deficiency is closely related to vas-
cular lesions. Except for higher BP, Ang II infusion to endo-
thelial VDR deficient mice caused increased vascular fibro-
sis and thickening of the aortic wall, as well as a higher level
of fetal genes expression in left ventricular myocardium and
higher expression of hypertrophic marker genes . On a
high fat diet, compared with vitamin D sufficient mice, vita-
min D deficient mice had 2-8-fold greater atherosclerosis in
the thoracic and abdominal aorta, and 2-fold greater athero-
sclerosis in the aortic arch, which is associated with the acti-
vation of macrophage endoplasmic reticulum stress and the
alteration of macrophage subtype . Vitamin D defi-
ciency promoted inward hypertrophic remodeling through
motivating VSMC proliferation, as well as intensified vessel
tone through the elevated vasoconstrictor prostanoid levels,
indicating vitamin D plays a role in cerebral artery geometry
and function . What’s more, in vitro, VDR was transi-
tory expressed during myeloid angiogenic cell differentia-
tion, and calcitriol enhanced differentiation of myeloid pro-
genitor cells into myeloid angiogenic cells and increased the
angiogenic capacity of myeloid angiogenic cell .
6. THE EFFECT OF VITAMIN D SUPPLEMENTA-
TION TO HYPERTENSION
6.1. Clinical Trials
Vitamin D deficiency is an independent risk factor for
hypertension. Some clinical trials have confirmed that vita-
min D supplementation is beneficial for patients with hyper-
tension, especially those coupling with vitamin D deficiency.
A study from the United States has demonstrated that 3
months of oral vitamin D3 supplementation significantly re-
duced SBP within unselected blacks. For each 1 ng/mL
greater increase in 25(OH)D level, SBP will reduce 0.2-mm
Hg significantly . Sluyter et al. found that high doses
vitamin D supplementation for 1 year lowered central BP
parameters but did not significantly change brachial BP
among adults with vitamin D deficiency. Nevertheless, this
supplementation had little effect on BP parameters in the
total sample .
However, the results were not all good. Some trials found
that vitamin D supplementation had no significant effect on
BP in non-hypertensive people [73, 135]. Some other were
conducted in people with hypertension, but also showed the
similar results [136, 137]. These inconsistent results could be
attributed to suboptimal experimental design, research popu-
Fig. (2). The mechanistic link s between vitamin D and BP. Vitamin D and VDR regulate BP mainly by suppressing vasoconstriction and
promoting vasodilatation. Vitamin D decreases the production of RAAS components and the activity of RAAS. What’s more, vitamin D
improves vascular function directly or indirectly. Vitamin D can increase vascular tone. Furthermore, Vitamin D restrains oxidative stress
and inflammation response thus repairing endothelial dysfunction and retarding atherosclerosis. Insulin resistance reduces arteriole relaxa-
tion, which can be suppressed by vitamin D.
990 Current Protein and Peptide Science, 2019, Vol. 20, No. 10 Lin et al.
lation selection, initial BP status, diversity in vitamin D dos-
age, used form of vitamin D component, treatment cycle,
season, or other facgtors. Future trials need to optimize the
experiment design, prolong follow-up periods and take the
effect of metabolism on the biological effects into account.
Importantly, measurement of potential biological or bio-
chemical indexes of vitamin D should be standardized to
allow pooling of research data .
6.2. Hypervitaminosis D and Rational Drug Use
Only a few studies have reported that excess vitamin D
supplementation can also cause high BP. In animal studies,
hypervitaminosis D is often used in conjunction with nico-
tine to create models of vascular calcium overload, which
causes isolated systolic hypertension, arterial stiffness and
kidney failure [138-140]. Mirhosseini et al. found both vita-
min D deficiency and toxicity can increase SBP and arterial
stiffness in rats, indicating the dose-response curve of ad-
verse cardiovascular effect to vitamin D was U-shaped .
Cases of vitamin D intoxication in human are on the rise,
largely due to the over-the-counter vitamin D supplement.
Patients who take or inject a large amount of vitamin D for a
long time will have hypercalcemia, hyperphosphatemia, kid-
ney stone or renal failure, extensive vascular calcification,
and what’s more, some patients will suffer from hyperten-
For the type of vitamin D supplement, vitamin D3 is
more effective in improving serum 25(OH)D concentration
than vitamin D2 . Compared with vitamin D3,
25(OH)D3 supplementation led to a safer, more immediate
and sustained rise in serum 25(OH)D levels, as well as a 5.7-
mm Hg decrease in SBP . About the optimal dose of
vitamin D for lowering BP, a clinical trial found that 2000
international unit (IU) of vitamin D per day as an add-on to
nifedipine showed significant antihypertensive effect .
Another showed that 4000IU/d of cholecalciferol are better
than 2000U/d and 1000IU/d . For all this, due to the
difference of individual's sensitivity to vitamin D, the opti-
mal dose should vary with each individual to achieve optimal
plasma 25(OH)D levels. However, both lower and upper
thresholds of plasma 25(OH)D levels for maintaining normal
BP are not clear at present. This still requires further explora-
Increased evidence suggests that vitamin D levels are
closely linked to BP. Through a series of experiments, we
found that vitamin D and VDR regulate BP in many ways
(Fig. 2). Vitamin D deficiency can increase risk of high BP
and aggravate hypertensive organ damage. According to the
evidence provided in this review, vitamin D was more effec-
tive in lowering BP in patients with hypertension and vita-
min D deficiency than in the general population. But vitamin
D can play a role in the physiological mechanisms associated
with BP and CVD in healthy people, involving the inhibition
of RAAS activation, the repair of endothelial function, and
In conclusion, vitamin D and VDR play a certain role in
the treatment of hypertension. Whether vitamin D can be
used as a biomarker or a conventional therapeutic drug of
hypertension remains to be tested experimentally. And the
guidelines for vitamin D supplementation in clinical prac-
tices or in people who are at risk for hypertension also need
to be explored.
CONSENT FOR PUBLICATION
This work received support by National Nature Science
Foundation of China grant No’s. 81473653 and 81774242.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
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