Cardiovascular Research Advance Access originally published online on December 16, 2008
Cardiovascular Research 2009 81(2):237-239; doi:10.1093/cvr/cvn345
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vascular smooth muscle cells sense calcium: a new paradigm in vascular calcification
Kidney Research Centre, Research Institute, University of Ottawa/Ottawa Health, 451 Smyth Rd, Ottawa, ON, KIH 8M5 Canada
* Corresponding author. Tel: +1 613 562 5800; fax: +1 613 562 5487. E-mail address: rtouyz{at}uottawa.ca
This editorial refers to ‘Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells’ by Alam et al.,10 pp. 260–268, this issue.
Calcification of arteries is a complex and dynamic process frequently seen in atherosclerosis, diabetes, and chronic kidney disease. This phenomenon, now considered a distinct inflammatory arteriopathy, has important clinical significance because arterial calcification is associated with increased cardiovascular events and is a strong predictor of poor cardiovascular outcomes.1,2 Patients with high coronary artery calcification scores have a five- to seven-fold increase in the risk of a hard coronary event compared with patients with low calcium scores, and patients with chronic kidney disease and vascular calcification have a 20- to 30-fold increase in cardiovascular mortality.2
Arterial calcification is a pathological process involving the vascular media and adventitia.3 Medial vascular smooth muscle cells (VSMCs) lose their ability to express smooth muscle-specific markers and undergo phenotypic transformation to osteoblast-like cells. Perivascular adventitial cells, microvascular pericytes, and adventitial mesenchymal stem cells also have the potential to express osteoblastic transcription factors, suggesting that, in addition to VSMCs, other vascular cell types contribute to calcification. The course of vascular calcification shares many features with that of bone mineralization, except that whereas skeletal mineralization is a physiological and highly regulated process, vascular calcification is a pathological phenomenon associated with extraskeletal mineralization in the vascular wall.2,3 Passive calcium phosphate deposition, active cell-mediated processes, and inflammatory responses contribute to vascular calcification.4–7 Of the many cellular regulators, the bone morphogenic proteins (BMP) seem to be particularly important.7 BMP-2/BMP-4 binds the BMPR1/BMPR2 receptor complex and activates the Smad signalling pathway, which induces expression of transcription factors Cbfa1, osterix, and MSX-2. BMP-4 also stimulates the generation of reactive oxygen species. These events lead to a phenotypic change in VSMCs to an osteogenic phenotype, which expresses alkaline phosphatase and produces hydroxyapatite crystals. Calcification inhibitors such as fetuin-A, MGP, osteoprotegerin, osteopontin, BMP-7, and Smad 6 antagonize BMP-2/BMP-4 signalling and inhibit vascular calcification.4,5,8 Many other factors, both stimulatory and inhibitory, have also been implicated in vascular calcification (Table 1), indicating the complexity of the process.7–9
|
In the current issue of the Journal, Alam et al.10 extend our knowledge on the pathobiology of vascular calcification by demonstrating a putative role for the extracellular calcium-sensing receptor (CaR). The CaR, a G protein-coupled receptor, is expressed primarily in the parathyroid glands, kidney, and bone, where it plays an important role in calcium homeostasis.11 The CaR senses alterations in the level of extracellular calcium and responds with changes in function that are directed at normalizing the blood calcium concentration. In the parathyroid gland, CaR modulates parathyroid hormone (PTH) secretion by inhibiting release when extracellular Ca2+ is high and stimulating release when extracellular Ca2+ is low. Activation of bone CaRs leads to bone osteoblast activation (bone anabolic effect), while osteoclasts undergo apoptosis (anti-resorption). The importance of CaR in clinical medicine is clearly evident because various mutations of the CaR gene give rise to gain or loss of functions leading to hypo- or hypercalcaemic conditions, respectively.12 Calcimimetic CaR activators and calcilytic CaR antagonists have been developed with potential for use in the treatment of disorders associated with hyper- and hypo-calcemia, respectively.
What is intriguing in the study of Alam et al.10 is the demonstration that VSMCs possess functionally active CaRs which, when dysregulated, may play a role in vascular calcification. This is supported by the findings that (i) the expression of CaR was reduced when VSMCs deposited a mineralized matrix, a response that was exaggerated in experimental conditions that mimic those in hypercalcaemic chronic kidney patients, and (ii) calcified areas of atherosclerotic tibial arteries from patients exhibited a marked decreased in CaR expression compared with normal internal mammary arteries. Although previous studies have shown that CaR is present in the vasculature,13–15 this is the first demonstration that CaR is downregulated in human calcified arteries and in mineralized VSMCs. Moreover, it is shown that the stimulation of CaRs with calcimimetics, which act as allosteric modulators of the CaR, attenuates VSMC mineralization.
Findings from this paper10 need to be interpreted within the context of the experimental design. There are some aspects of the study that necessitate further consideration. First, although the presence of CaR in VSMCs is clearly demonstrated, the physiological significance, the functional role, and regulatory mechanisms are not defined. It is possible that CaRs are necessary to maintain the VSMC phenotype, but this still needs to be proven. Secondly, the signalling pathways through which CaRs mediate vascular effects were not identified. Although CaR activation by Ca2+ induced phosphorylation of the kinase ERK1/2 in VSMCs, it is unclear whether this pathway is involved in mineralization when CaR is downregulated. In other cell types, CaRs are located in caveolae and signal through G
q/11 or Gi/0 to activate the phospholipases PLA2, PLD, and PLC and the protein kinases PKC, PI3K, and mitogen-activated protein kinases.1,12 Whether similar pathways are activated in VSMCs and whether they are associated with pro-or anti-mineralization processes await clarification. Thirdly, to evaluate whether the findings observed in cell culture have pathophysiological significance, it would be important to test the system in animal models with chronic kidney disease and vascular calcification. Finally, it is still unclear as to whether calcification is a cause or a consequence of CaR downregulation in VSMCs.
Despite these limitations, the study by Alam et al.10 provides new insights into the possible mechanisms contributing to vascular calcification through VSMC CaR. It is suggested that conditions associated with hypercalcaemia and hyperphosphataemia, as they occur in chronic kidney disease, induce the loss of functional vascular CaRs, which promotes mineral deposition by VSMCs and consequent vascular media calcification, and that this effect can be normalized by calcimimetics. By directly targeting the CaR in VSMCs, calcimimetics may facilitate CaR function, thereby ameliorating VSMC mineralization and vascular damage associated with CaR downregulation. These effects could normalize CaR function and prevent osteogenic transformation of VSMCs. These provocative findings have important clinical implications, because the use of calcimimetics in diseases associated with hypercalcaemia and/or ectopic calcification may reduce vascular calcification and associated risks. Future studies to address these possibilities are certainly warranted, as they provide novel targets and interesting strategies in the management of patients with atherosclerosis, chronic kidney disease, and diabetic vascular disease.
 |
Acknowledgements |
|---|
R.M.T. is supported through a Canada Research Chair/Canadian Foundation for Innovation award. A.C.M. received a fellowship from Amgen.
Conflict of interest: none declared.
|
Notes |
|---|
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
|
References |
|---|
 Top References |
|---|
- Guzman RJ. Clinical, Cellular, and molecular aspects of arterial calcification. J Vasc Surg (2007) 45(Suppl. A):A57–A63.[CrossRef][Medline]
- London GM, Marchais SJ, Guérin AP, Métivier F. Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia. Curr Opin Nephrol Hypertens (2005) 14:525–531.[Web of Science][Medline]
- Cozzolino M, Mazzaferro S, Pugliese F, Brancaccio D. Vascular calcification and uremia: what do we know? Am J Nephrol (2008) 28:339–346.[CrossRef][Web of Science][Medline]
- Weissen-Plenz G, Nitschke Y, Rutsch F. Mechanisms of arterial calcification: spotlight on the inhibitors. Adv Clin Chem (2008) 46:263–293.[CrossRef][Web of Science][Medline]
- Moe SM, Reslerova M, Ketteler M, O'Neill K, Duan D, Koczman J, et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int (2005) 67:2295–2304.[CrossRef][Web of Science][Medline]
- Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM. Exploring the biology of vascular calcification in chronic kidney disease: what's circulating? Kidney Int (2008) 73:384–390.[CrossRef][Web of Science][Medline]
- Griethe W, Schmitt R, Jurgensen JS, Bachmann S, Eckardt KU, Schindler R. Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis. J Nephrol (2003) 16:728–732.[Web of Science][Medline]
- Suliman ME, García-López E, Anderstam B, Lindholm B, Stenvinkel P. Vascular calcification inhibitors in relation to cardiovascular disease with special emphasis on fetuin-A in chronic kidney disease. Adv Clin Chem (2008) 46:217–262.[CrossRef][Web of Science][Medline]
- Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation (2007) 116:85–97.
[Abstract/Free Full Text] - Alam M, Kirton JP, Wilkinson FL, Towers E, Sinha S, Rouhi M, et al. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovasc Res (2009) 81:260–268.
[Abstract/Free Full Text] - Yamaguchi T. The calcium-sensing receptor in bone. J Bone Miner Metab (2008) 26:301–311.[CrossRef][Web of Science][Medline]
- Egbuna OI, Brown EM. Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol (2008) 22:129–148.[CrossRef][Medline]
- Molostvov G, James S, Fletcher S, Bennett J, Lehnert H, Bland R, Zehnder D. Extracellular calcium-sensing receptor is functionally expressed in human artery. Am J Physiol Renal Physiol (2007) 293:F946–F955.
[Abstract/Free Full Text] - Fryer RM, Segreti JA, Widomski DL, Franklin PH, Banfor PN, Koch KA, et al. Systemic activation of the calcium sensing receptor produces acute effects on vascular tone and circulatory function in uremic and normal rats: focus on central versus peripheral control of vascular tone and blood pressure by cinacalcet. J Pharmacol Exp Ther (2007) 323:217–226.
[Abstract/Free Full Text] - Weston AH, Absi M, Harno E, Geraghty AR, Ward DT, Ruat M, et al. The expression and function of Ca(2 + )-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes. Br J Pharmacol (2008) 154:652–662.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Related Article
- Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells
- Masih-ul Alam, John Paul Kirton, Fiona L. Wilkinson, Emily Towers, Smeeta Sinha, Mansour Rouhi, Thomas N. Vizard, Andrew P. Sage, David Martin, Donald T. Ward, Marie Yvonne Alexander, Daniela Riccardi, and Ann E. Canfield
Cardiovasc Res 2009 81: 260-268.[Abstract] [Full Text] [PDF]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||