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4 Direct Effects of Vitamin D on Vascular Calcification: Lessons from In Vitro Models

4 Direct Effects of Vitamin D on Vascular Calcification: Lessons from In Vitro Models

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366



L. Hénaut et al.



a



b



21



367



Vitamin D and Cardiovascular Calcification in Chronic Kidney Disease



Systemic compartment



Vitamin D



Optimal concentration (1 nmol/L)



2

Transient increase

in Ca × P



3



5

4



1

CaSR expression

Pi-induced

osteogenic transition



Cardiovascular

calcification

Cardiovascular system



6



7



8



Local

inflammation

Systemic

inflammation

(TNF-a, IL-6, IL-1b)



Vascular and systemic

levels of klotho



Vascular and systemic

levels of osteopontin



Secondary

hyperparathyroidism



Fig. 21.2 The complexity of vitamin D’s effects on vascular calcification. Red lines illustrate

effects of vitamin D that promote vascular calcification, whereas green lines represent anticalcifying effects. Vitamin D directly favors Pi-induced vascular smooth muscle cells (VSMC)

calcification (1) and indirectly promotes elevation of the circulating Ca x Pi product concentration

by enhancing absorption of the two from the intestinal tract (2). Vitamin D receptor activators

(VDRAs) possess anti-calcific properties because they favor calcium-sensing receptor (CaSR)

expression (3), decrease systemic inflammation (4) and protect against the latter’s direct, procalcific effects (5). VDRAs supplementation also favors both vascular and systemic expression of

klotho (6) and osteopontin (7), which are known to have anti-calcific properties. Lastly, VDRAmediated reduction of circulating PTH levels (8) is involved in the regulation control of secondary

hyperparathyroidism (SHPT), preventing the further development of vascular calcification



enzymes such as 25-hydroxylase, 1-alpha-hydroxylase and 24-hydroxylase. Given

that (i) 1α-hydroxylase’s low affinity for 25(OH)D is compensated for by higher

circulating concentrations and (ii) 1α-hydroxylase is found in many tissues (other

than the kidneys), both 25(OH)D and 1,25(OH)D have a significant effect on VDR

activation despite CKD-related vitamin D deficiency. Interestingly, both the VDR

and 1α-hydroxylase are expressed in cells found in the vasculature (e.g. VSMCs,

endothelial cells and monocytes) – suggesting that calcitriol may have an autocrine

role within the vascular wall in general and with regard to vascular calcification in

particular (as suggested by in vitro studies).



Fig. 21.1 A schematic representation of vitamin D’s varying effects on vascular calcification.

Increasing vascular concentrations of calcitriol are shown on the x-axis and increasing vascular

calcification (VC) is shown on the y-axis. Vascular calcification develops in the presence of abnormally low or abnormally high concentrations of calcitriol, resulting in a U-shaped correlation. (a)

Evidence from clinical studies and in vivo animal studies of a U-shaped correlation between vitamin D status and the development of vascular calcification. (b) The U-shaped curve for vitamin D

results from a number of complex local and systemic processes



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L. Hénaut et al.



In vitro, exposure of VSMCs to calcitriol does not induce calcification in the

absence of a calcifying agent such as calcium or phosphate. The first study of this

subject found that high calcitriol concentrations (>10 nmol/L) increased

β-glycerophosphate-induced VSMCs calcification in vitro in a concentrationdependent manner. This effect was associated with (i) an increase in osteopontin

expression and ALP activity, and (ii) a decrease in the secretion of PTH-related

protein (an endogenous inhibitor of vascular calcification) [51]. Accordingly, high

calcitriol concentrations also favoured the phosphate-induced overexpression of

osteogenic markers such as bone morphogenetic protein 2 (BMP2), runx2, msx2,

osteocalcin and osterix [52, 53]. Under high calcitriol concentrations, VDR was also

found to bind to the transcription factor runx2 and thereby induce the osteogenic

transformation of VSMCs [54]. In VSMCs cultured in vitro, high doses of calcitriol

increase the expression of RANK-L [41], which is known to directly regulate

VSMCs calcification by inducing BMP-4 expression through the alternative NF-kB

pathway [55]. Furthermore, calcitriol increases VDR expression in VSMCs, which

could amplify local effects. Even though most studies to date have linked high calcitriol concentrations to calcification, other studies have not observed any additive

effects on phosphate-induced mineralization [56]. It is noteworthy that the addition

of paricalcitol to high-phosphate medium not only reduced calcification but also

downregulated the expression of BMP2 and other osteoblastic phenotype markers,

which was not found with high calcitriol concentrations [41, 53]. This finding suggests that in addition to a dose effect, other factors are involved (depending on the

type of vitamin D derivative).

The CaSR is a G-protein-coupled receptor expressed by parathyroid gland cells

in particular. Activation of the CaSR by allosteric modulators (such as cinacalcet

HCl) reduces serum PTH, Ca2+0 and Pi concentrations in dialyzed CKD patients and

enables better control of SHPT [57], which may reduce the development of vascular

calcification [58, 59]. Given that we and Molostvov et al. reported that the CaSR is

expressed and functionally active in the vasculature [60], it is possible that calcimimetics have a direct effect on the vascular CaSR. We and others have demonstrated

that an increase in CaSR expression protects against VSMCs calcification [61–63].

The mechanism has not yet been fully characterized but may involve a reduction in

collagen type I secretion and BMP2 expression and an increase in MGP production.

The low vascular expression of CaSR in CKD constitutes an additional calcifying

factor. Studies of parathyroid, thyroid, and kidney cells have mapped VDR binding

sites within two CaSR promoters [64]. In a recent study, we demonstrated that local

exposure of human VSMCs to calcitriol at an optimal concentration (1 nmol/L)

upregulates CaSR biosynthesis through VDR activation [65]. In turn, this increases

the CaSR’s availability at the cell surface and thereby its local protective effect

against high-Ca2+0-induced calcification. These protective effects were centred on

nanomolar concentrations, and any change in either direction by a factor of 10 or

more caused a loss of calcitriol’s beneficial effect. The U-shaped dose-dependent

response observed in this study might explain (at least in part) the apparently paradoxical associations between cardiovascular calcification and both abnormally high

and abnormally low serum 1,25(OH)2D or 25(OH)D concentrations.



21



Vitamin D and Cardiovascular Calcification in Chronic Kidney Disease



369



Systemic inflammation is a common feature of CKD [66] and accelerates the

progression of cardiovascular calcification [67]. The inflammation marker C-reactive

protein has been identified as an independent risk factor for cardiovascular morbidity

and mortality in ESRD patients [68]. The circulating level of tumour necrosis factor

(TNF) receptor 1 is also a strong prognostic factor for all-cause mortality in type II

diabetes with renal dysfunction [69]. Interaction between members of the TNF superfamily and their receptors elicits several biological effects involved in the development of cardiovascular calcification. In vitro, TNF-α promotes Pi-induced VSMCs

mineralization and osteogenic transformation [70, 71], apoptosis [72], endoplasmic

reticulum stress, and Pi entry into VSMCs [73], whereas it decreases the availability

of the vascular calcification inhibitor PPi [74]. TNF-α also favours the onset of calcification in valve myofibroblasts [75]. Both calcitriol and maxacalcitol were shown to

abrogate the acceleration of the osteogenic process induced by phosphate and TNF-α

in VSMCs in a concentration-dependent manner, through a decrease in runx2 and

MMP2 expression [76]. In another study, paricalcitol was more potent than calcitriol

in reducing the mineralization induced by Pi and TNF-α [77].

Taken as a whole, these data suggest that vitamin D compounds could directly

and dose-dependently regulate the osteogenic transition of VSMCs. Despite all the

evidence from in vitro studies, the presence of the VDR in VSMCs in vivo is still

subject to debate [78].



21.5



Systemic and Indirect Effects of Vitamin D

on Vascular Calcification



In addition to their direct vascular effects, VDRAs regulate more than 300 genes in

all cell types. Accordingly, supplementation with VDRAs impacts the function of

the main organs involved in Ca/P homeostasis (i.e. the intestine, kidney, bones and

parathyroid gland) and thus affects cardiovascular calcification. It is particularly

important to note that VDRAs stimulate calcium and phosphate absorption by the

intestines if dietary content is low diet [79]. VDRAs also decrease calcium and

phosphate reabsorption in the kidneys and can thus trigger transient or even chronic

episodes of hypercalcemia or hyperphosphatemia [80]; in turn, this promotes mineral deposition in the vasculature. Lastly, VDRAs indirectly prevent cardiovascular

calcification by lowering high PTH levels, which are often associated with high

calcification scores [81] as a consequence of SHPT.

VDRAs supplementation also impacts inflammation, which is indirectly involved

in the formation of cardiovascular calcification. High circulating levels of inflammation markers (such as CRP, TNF-α and interleukin-6 (IL-6)) are known to be

associated with (i) higher levels of the bone mineral metabolism markers FGF23

and ALP, and (ii) increased prevalence, severity and progression of vascular calcification [82, 83]. Elevated serum levels of CRP, TNF-α, IL-1β and IL-6 have been

reported in haemodialysis patients [84], and serum IL-6 levels are elevated in haemodialysis patients with aortic intimal and medial calcification [85] and are



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predictive of death [86]. Recently, the upregulation of mitogen-activated protein

kinase phosphatase-1 by vitamin D was identified as a novel pathway by which

vitamin D inhibits lipopolysaccharide (LPS)-induced p38 activation and cytokine

production by monocytes and macrophages [87]. In accordance with this observation, treatment with vitamin D and its analogues was shown to lower serum levels

of CRP, TNF-α, IL-1β and IL-6 in haemodialysis patients [88–91]. As discussed

above, TNF-α is a strong inducer of Pi-induced VSMCs calcification and is also

involved in the onset of valve myofibroblast calcification. In addition to the direct

protective effect of calcitriol on the TNF-α-induced osteogenic transition in VSMCs,

VDRAs are known to act in a paracrine manner to promote a pro-calcific to anticalcific phenotypic transition in macrophages. The latter phenotype is characterized

by low production of TNF-α and elevated levels of osteopontin (an inhibitor of calcification), which strongly reduces the VSMC calcification induced by co-culture

with macrophages [92]. IL-1β was shown to promote MMP expression in calcific

aortic valve stenosis [93]. Furthermore, mice lacking the IL-1β inhibitor IL-1Ra

were shown to develop aortic stenosis and proximalis calcification [94]. IL-6 is a

strong inducer of RANKL, and vice versa [95]. Neutralization of IL-6 reversed the

RANKL-dependent regulation of osteopontin, runx2 and BMP2 in cultured VSMCs

isolated from ApoE–/– OPG–/– mice [95]. In cultured human VICs, high Pi was associated with greater IL-6 secretion [96]. Pi-induced mineralization was strongly

dependent on IL-6 expression in the latter study, since IL-6 blockade by siRNA

decreased VICs calcification. Indeed, IL-6 increased the expression of osteoblastic

genes (including runx2 and osteopontin) in cultured human VICs. Thus, by modulating the vascular response to inflammation, vitamin D sterols might interfere with

vascular calcification. To address this question, Guerrero et al. evaluated the impact

of vitamin D supplementation on systemic inflammation and the resulting vascular

calcification in uraemic rats fed with high-phosphorus diet. Treatment with LPS

increased plasma levels of TNF-α, monocyte chemotactic protein-1 and

interleukin-1α, and induced calcification. Concomitant treatment with paricalcitol

resulted in more marked anti-inflammatory effects than treatment with calcitriol. In

contrast to calcitriol, paricalcitol prevented vascular calcification [77]. These results

demonstrate that the potential anti-inflammatory effects associated with vitamin D

supplementation might interfere with the process of cardiovascular calcification and

therefore should not be neglected. Furthermore, they demonstrate that supplementation with various vitamin D analogues may affect vascular calcification to differing

extents.

The phosphaturic hormone FGF23 and its co-factor klotho have an essential role

in the control of phosphate and vitamin D metabolism. The klotho/FGF receptor-1

complex forms a specific receptor for FGF-23 signalling and mediates (in part)

FGF-23’s action [97]. In CKD, circulating levels of FGF23 increase dramatically as

renal function decreases, whereas tissue levels of klotho decline. Since klothodeficient mice and FGF23-null mice were shown to exhibit soft tissue calcification,

some researchers have suggested that dysregulation of the FGF23–klotho axis may

impact the progression of vascular calcification [98]. FGF23’s putative direct effect



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