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Circulation. 2005;111:1571-1573
doi: 10.1161/01.CIR.0000161830.45399.F6
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(Circulation. 2005;111:1571-1573.)
© 2005 American Heart Association, Inc.

Editorial

A New "Sunshine" in the Vasculature?

Markus M. Bachschmid, PhD; Bernd van der Loo, MD

From the Department of Biology (M.M.B.), University of Konstanz, Konstanz, Germany, and the Division of Cardiology (B.v.d.L.), Cardiovascular Centre, University Hospital, Zurich, Switzerland.

Correspondence to Bernd van der Loo, MD, Division of Cardiology, Cardiovascular Centre, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. E-mail bernd.vanderloo{at}usz.ch


Key Words: Editorials • molecular biology • vitamin D • vasculature • muscle, smooth

The discovery of vitamin D (calciol) was one of the great achievements in medicine and helped to eliminate rachitis in children and osteomalacia in adults. Vitamin D systemically acts on calcium homeostasis in parallel with parathyrin (parathyroid hormone [PTH]) and calcitonin to maintain serum calcium levels within the physiologically acceptable range. Vitamin D controls calcium and phosphate absorption in the intestine, calcium reabsorption in the kidney, and mineralization of bone.

See p 1666

Synthesis of vitamin D requires UVB irradiation of the skin, which promotes the metabolism of its precursor, 7-dehydrocholesterol, to previtamin D3, which then slowly isomerizes to form vitamin D3. Because exposure to sunlight is necessary for its synthesis, vitamin D has also been called the "sunshine" vitamin. Vitamin D has also been identified in archaic phytoplankton and zooplankton, where it is synthesized after solar UV exposure. Its function in these organisms is poorly understood, but it probably serves as a photosensor. This would imply an evolutionarily conserved cellular signal transduction pathway, mediating autocrine, paracrine, and endocrine signals.

Vitamin D3 is biologically inactive and must be hydroxylated, first in the liver to 25-hydroxyvitamin D3, and finally in the kidney by the 25-hydroxyvitamin D3-1{alpha}-hydroxylase (CYP24) enzyme system, to form the active metabolite 1{alpha},25-dihydroxyvitamin D3 [1{alpha},25-(OH)2D3; calcitriol].1 This also suggests that the term "vitamin" is possibly inappropriate, because its actions represent a classic steroidal hormone endocrine system.

Vitamin D (for simplicity, the term "vitamin D" is used to indicate its active metabolite) regulates myocyte proliferation and induces hypertrophy.2 Vitamin D may also cause calcification of vascular smooth muscle cells (VSMCs)3 in a dose-dependent manner. Its influence on peripheral arteries has recently been reviewed,4 and its role can be considered at least partly controversial (eg, its effect on blood pressure). Vitamin D is a negative regulator of the renin–angiotensin system by decreasing renin expression in the kidney.5 In vitamin D receptor (VDR)–null mice, renin levels are high, causing hypertension and cardiac hypertrophy. In parallel, inhibition of 1{alpha},25-(OH)2D3 synthesis increases renin activity, whereas 1{alpha},25-(OH)2D3 supplementation leads to its suppression. Some of its most important noncardiovascular effects are related to findings that vitamin D deficiency is linked to a higher prevalence of prostate, colon, and breast cancer and susceptibility to type I diabetes mellitus and some autoimmune diseases (for review, see Holick6).

Vitamin D can exist in 2 isoforms, which trigger rapid, nongenomic (6-s-cis) and genomic (6-s-trans) responses. The rapid, nongenomic effects include Ca2+ influx, release of intracellular Ca2+ from various stores, Ca2+ uptake in intestine (transcaltachia), activation of protein kinase C, opening of voltage-gated Ca2+ and Cl– channels, and modulation of adenylyl cyclase. These can all be modulated by alternative synthetic ligands [ie, triggered by the agonist 1{Delta},25(OH)2 lumisterol or antagonized by 1ß,25(OH)2D3].7 Observations in hypertensive patients strongly support the concept of rapid, nongenomic effects, because short-term infusion of 1{alpha},25-(OH)2D3 produces a transient increase in peripheral resistance.8 Furthermore, recent data suggest that VSMC migration induced by 1{alpha},25-(OH)2D3 requires the activation of phosphatidylinositol (PI) 3-kinase and that this activation is independent of gene transcription.7 Therefore, it seems that these actions require a rapid response by a putative, as-yet-unidentified, membrane receptor to mediate the nongenomic actions of 1{alpha},25-(OH)2D3. Thus, vitamin D rather appears to act as a modulator of structure and function. Its observed effects depend on the model, metabolic state, or experimental conditions used. Annexin II is one of the proteins identified to bind with high affinity to 1{alpha},25-(OH)2D3 bromoacetate.9

Genomic responses are mediated by a well-established member of the class II nuclear steroid hormone receptors (ie, VDR), which is closely related to the retinoic acid and thyroid hormone receptors.10 Thus, the receptor must form a heterodimeric complex with the retinoid receptor and bind on activation to the vitamin D–responsive element. As was the case for nongenomic effects, novel antagonists [(23S)- and (23R)-25-dehydro-1{alpha},OH-D3-26,23-lactone] were also synthesized to specifically alter genomic responses.11 Those may be of particular interest for potential pharmacological intervention.

Alternatively, the VDR could be linked to intracellular components of signal transduction pathways that could, in turn, interact with components of downstream pathways to mediate the rapid effects. This scenario could serve as an alternative explanation to the putative membrane receptor interaction described earlier. Interestingly, similar observations have been made for the estrogen receptor in endothelial cells.12 In that case, a small portion of the estrogen receptor seems to be localized in the cytosol and activates PI 3-kinase by binding to the PI 3-kinase regulatory subunit p85{alpha}.12 Furthermore, estrogen and androgen nuclear receptors of osteoblasts are involved in activation of the Src/Shc/ERK signaling pathway and lead to rapid attenuation of apoptosis without translocation to the nucleus.13

In addition to these observations, the presence of CYP24, which has recently been described in endothelial cells,14 and the new discovery of this key enzyme for the metabolism of Vitamin D in human VSMCs described by Somjen et al15 in this issue of Circulation, may reveal a significantly expanded role for vitamin D in the cardiovascular system. Obviously, one of the questions arising from this article will be if and to what extent the interactions between vitamin D and the vasculature are exerted via the circulating active metabolite or the active vitamin produced at its target cell. One may argue that production "on site" would enable the most rapid response to changes in the vasculature, thus facilitating local regulation. If the latter turns out to be true, although the possible downstream targets for VDR in the vascular wall are not yet completely identified, then it may be that this classic hormone exerts effects beyond the regulation of plasma calcium homeostasis in general and also far beyond the migration, growth, and calcification in VSMCs in particular. In this context, the inhibitory effect on both vascular endothelial growth factor (VEGF)–induced endothelial cell sprouting in the setting of angiogenesis16 and of prostacyclin (PGI2) release by induction of cyclooxygenase 2 (COX-2)17 have been described.

Although an endogenous 25-(OH)D3-1{alpha} hydroxylase system has now been demonstrated in human VSMCs, its full significance as a mediator of VSMC homeostasis and its full relevance for blood vessel function have yet to be established. The fact that release of PTH and phytoestrogens leads to upregulation of 25-(OH)D3-1{alpha} hydroxylase, as demonstrated by Somjen et al, may provide an explanation for the observation that both may act as vasodilators.

Interestingly, vitamin D has been found to trigger PGI2 synthesis in VSMCs and intact rat aortic segments.17 PGI2 is a vasoprotective mediator that prevents thrombus formation, cell adhesion, and SMC proliferation and that is crucially involved in maintaining vessel function by causing relaxation. After induction of COX-2, which can be triggered by vitamin D, PGI2 synthase, constitutively expressed in VSMCs, is provided with its substrate, thus mobilizing PGI2. Such a mechanism could probably compensate for the "dysfunctional endothelium" as is observed in sepsis and might explain the associated severe hypotension.18

The effects of vitamin D on VSMC proliferation are puzzling. VSMCs exhibited either a reduction or an increase in the rate of cell proliferation.19 Depending on the metabolic state (quiescent or nonquiescent), cell culture conditions, or type of stimulus (eg, thrombin, platelet-derived growth factor, serum), 1{alpha},25-(OH)2D3 is able to modulate VSMC growth in either way. In the study presented by Somjen et al, an increase in endogenous vitamin D synthesis in VSMCs by induction of 25-hydroxyvitamin D3-1{alpha} hydroxylase was observed after stimulation with native or synthetic phytoestrogen. Furthermore, in their model, increased levels of vitamin D caused a reduction of DNA synthesis.

The modulatory effects were further observed in a model of endothelin-stimulated hypertrophy of rat cardiac myocytes.20 Vitamin D alone reduced the expression of atrial natriuretic peptide, a marker for early hypertrophy, but when administered in combination with retinoic acid, the effect was potentiated. These heterogeneous effects could be explained by the heteromeric structure of the VDR.

With respect to the modulation of cardiovascular effects by 1{alpha},25-(OH)2D3, further investigations are needed that could eventually lead to novel pharmacological approaches to manage hypertrophy, restenosis, and atherosclerosis or remodel the cardiovascular system. In this context, identification of the precise intracellular locations of 25-(OH) vitamin D3-1{alpha} hydroxylase and the sites of production of the active vitamin D3 metabolite should be pursued. It is known to be expressed in the mitochondria of renal cells,21 but nothing is known so far about its location in VSMCs. Vitamin D has recently been shown to augment the drop in mitochondrial membrane potential induced by tumor necrosis vector in breast cancer cells.22 It will be interesting to see whether the mitochondria become a target of vitamin D action, which in this case, is likely to be a detrimental effect. Finally, it will be important to determine which pathways induce and mediate expression and activity of this enzyme. Further research into the molecular mechanisms of actions of vitamin D will be needed for more profound insights into its potential protective (and its potential harmful) effects on the cardiovascular system, probably only partly elucidated to date. The article by Somjen et al in this issue is an important additional link in this chain.


*    Footnotes
 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

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Related Article:

25-Hydroxyvitamin D3-1{alpha}-Hydroxylase Is Expressed in Human Vascular Smooth Muscle Cells and Is Upregulated by Parathyroid Hormone and Estrogenic Compounds
Dalia Somjen, Yosef Weisman, Fortune Kohen, Batya Gayer, Rona Limor, Orly Sharon, Niva Jaccard, Esther Knoll, and Naftali Stern
Circulation 2005 111: 1666-1671. [Abstract] [Full Text]




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