SpringerLink
Log in

Role of the extracellular ATP/pyrophosphate metabolism cycle in vascular calcification

  • Review Article
  • Published:
Purinergic Signalling Aims and scope Submit manuscript

Abstract

Conventionally, ATP is considered to be the principal energy source in cells. However, over the last few years, a novel role for ATP as a potent extracellular signaling molecule and the principal source of extracellular pyrophosphate, the main endogenous inhibitor of vascular calcification, has emerged. A large body of evidence suggests that two principal mechanisms are involved in the initiation and progression of ectopic calcification: high phosphate concentration and pyrophosphate deficiency. Pathologic calcification of cardiovascular structures, or vascular calcification, is a feature of several genetic diseases and a common complication of chronic kidney disease, diabetes, and aging. Previous studies have shown that the loss of function of several enzymes and transporters involved in extracellular ATP/pyrophosphate metabolism is associated with vascular calcification. Therefore, pyrophosphate homeostasis should be further studied to facilitate the design of novel therapeutic approaches for ectopic calcification of cardiovascular structures, including strategies to increase pyrophosphate concentrations by targeting the ATP/pyrophosphate metabolism cycle.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Data not available to be shared.

References

  1. Chen NX, Moe SM (2015) Pathophysiology of vascular calcification. Curr Osteoporos Rep 13(6):372–380

    Article  CAS  PubMed  Google Scholar 

  2. Rocha-Singh KJ, Zeller T, Jaff MR (2014) Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv 83(6):E212-220

    Article  PubMed  Google Scholar 

  3. Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM (2011) Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res 109(6):697–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rutsch F, Nitschke Y, Terkeltaub R (2011) Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel. Circ Res 109(5):578–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Urry DW (1971) Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis. Proc Natl Acad Sci U S A 68(4):810–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zimmermann H, Zebisch M, Sträter N (2012) Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 8(3):437–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 362(4–5):299–309

    Article  CAS  PubMed  Google Scholar 

  8. Villa-Bellosta R, Sorribas V (2013) Prevention of vascular calcification by polyphosphates and nucleotides- role of ATP. Circ J 77(8):2145–2151

    Article  CAS  PubMed  Google Scholar 

  9. Villa-Bellosta R (2019) ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A 116(47):23698–23704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31(4):607–617

    Article  CAS  PubMed  Google Scholar 

  11. LeGeros RZ (2001) Formation and transformation of calcium phosphates: relevance to vascular calcification. Z Kardiol 90(Suppl 3):116–124

    PubMed  Google Scholar 

  12. Johnsson MS, Nancollas GH (1992) The role of brushite and octacalcium phosphate in apatite formation. Crit Rev Oral Biol Med Off Publ Am Assoc Oral Biol 3(1–2):61–82

    Article  CAS  Google Scholar 

  13. Kay MI, Young RA, Posner AS (1964) Crystal structure of hydroxyapatite. Nature 204:1050–1052

    Article  CAS  PubMed  Google Scholar 

  14. Villa-Bellosta R, Millan A, Sorribas V (2011) Role of calcium-phosphate deposition in vascular smooth muscle cell calcification. Am J Physiol Cell Physiol 300(1):C210-220

    Article  CAS  PubMed  Google Scholar 

  15. Villa-Bellosta R (2018) Synthesis of extracellular pyrophosphate increases in vascular smooth muscle cells during phosphate-induced calcification. Arterioscler Thromb Vasc Biol 38(9):2137–2147

    Article  CAS  PubMed  Google Scholar 

  16. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K et al (2000) Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87(7):E10-17

    Article  CAS  PubMed  Google Scholar 

  17. Proudfoot D, Skepper JN, Hegyi L, Bennett MR, Shanahan CM, Weissberg PL (2000) Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 87(11):1055–1062

    Article  CAS  PubMed  Google Scholar 

  18. Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A et al (2008) Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 118(17):1748–1757

    Article  CAS  PubMed  Google Scholar 

  19. Speer MY, Li X, Hiremath PG, Giachelli CM (2010) Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis. J Cell Biochem 110(4):935–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sage AP, Lu J, Tintut Y, Demer LL (2011) Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int 79(4):414–422

    Article  CAS  PubMed  Google Scholar 

  21. Schibler D, Russell RG, Fleisch H (1968) Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats. Clin Sci 35(2):363–372

    CAS  PubMed  Google Scholar 

  22. Lomashvili KA, Khawandi W, O’Neill WC (2005) Reduced plasma pyrophosphate levels in hemodialysis patients. J Am Soc Nephrol 16(8):2495–2500

    Article  CAS  PubMed  Google Scholar 

  23. Villa-Bellosta R, Sorribas V (2011) Calcium phosphate deposition with normal phosphate concentration. Role of pyrophosphate. Circ J. 75(11):2705–10

    Article  CAS  PubMed  Google Scholar 

  24. Lomashvili KA, Narisawa S, Millán JL, O’Neill WC (2014) Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney Int 85(6):1351–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Villa-Bellosta R, O’Neill WC (2018) Pyrophosphate deficiency in vascular calcification. Kidney Int 93(6):1293–1297

    Article  CAS  PubMed  Google Scholar 

  26. Azpiazu D, González-Parra E, Egido J, Villa-Bellosta R (2018) Hydrolysis of extracellular pyrophosphate increases in post-hemodialysis plasma. Sci Rep 8(1):11089

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Váradi A et al (2014) ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol 34(9):1985–1989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Villa-Bellosta R, Rivera-Torres J, Osorio FG, Acín-Pérez R, Enriquez JA, López-Otín C et al (2013) Defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatment. Circulation 127(24):2442–2451

    Article  CAS  PubMed  Google Scholar 

  29. Pomozi V, Brampton C, van de Wetering K, Zoll J, Calio B, Pham K et al (2017) Pyrophosphate supplementation prevents chronic and acute calcification in ABCC6-deficient mice. Am J Pathol 187(6):1258–1272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. O’Neill WC, Lomashvili KA, Malluche HH, Faugere M-C, Riser BL (2011) Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int 79(5):512–517

    Article  PubMed  Google Scholar 

  31. Riser BL, Barreto FC, Rezg R, Valaitis PW, Cook CS, White JA et al (2011) Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 26(10):3349–3357

    CAS  Google Scholar 

  32. Dedinszki D, Szeri F, Kozák E, Pomozi V, Tőkési N, Mezei TR et al (2017) Oral administration of pyrophosphate inhibits connective tissue calcification. EMBO Mol Med 9(11):1463–1470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kozák E, Fülöp K, Tőkési N, Rao N, Li Q, Terry SF et al (2022) Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum. Exp Dermatol 31(4):548–555

    Article  PubMed  Google Scholar 

  34. Lohman AW, Billaud M, Isakson BE (2012) Mechanisms of ATP release and signalling in the blood vessel wall. Cardiovasc Res 95(3):269–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jansen RS, Küçükosmanoglu A, de Haas M, Sapthu S, Otero JA, Hegman IEM et al (2013) ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A 110(50):20206–20211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H et al (2000) Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 25(2):228–231

    Article  CAS  PubMed  Google Scholar 

  37. Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D et al (2000) Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 25(2):223–227

    Article  PubMed  Google Scholar 

  38. Villa-Bellosta R, Wang X, Millán JL, Dubyak GR, O’Neill WC (2011) Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle. Am J Physiol Heart Circ Physiol 301(1):H61-68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Höhne W et al (2003) Mutations in ENPP1 are associated with «idiopathic» infantile arterial calcification. Nat Genet 34(4):379–381

    Article  CAS  PubMed  Google Scholar 

  40. Rutsch F, Buers I, Nitschke Y (2021) Hereditary disorders of cardiovascular calcification. Arterioscler Thromb Vasc Biol 41(1):35–47

    CAS  PubMed  Google Scholar 

  41. Johnson K, Polewski M, van Etten D, Terkeltaub R (2005) Chondrogenesis mediated by PPi depletion promotes spontaneous aortic calcification in NPP1-/- mice. Arterioscler Thromb Vasc Biol 25(4):686–691

    Article  CAS  PubMed  Google Scholar 

  42. St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F et al (2011) NT5E mutations and arterial calcifications. N Engl J Med 364(5):432–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li Q, Price TP, Sundberg JP, Uitto J (2014) Juxta-articular joint-capsule mineralization in CD73 deficient mice: similarities to patients with NT5E mutations. Cell Cycle Georget Tex 13(16):2609–2615

    Article  CAS  Google Scholar 

  44. Narisawa S, Yadav MC, Millán JL (2013) In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin. J Bone Miner Res Off J Am Soc Bone Miner Res 28(7):1587–1598

    Article  CAS  Google Scholar 

  45. Lomashvili KA, Garg P, Narisawa S, Millan JL, O’Neill WC (2008) Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification. Kidney Int 73(9):1024–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. ** H, St Hilaire C, Huang Y, Yang D, Dmitrieva NI, Negro A et al (2016) Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. Sci Signal. 9(458):ra121

    Article  PubMed  PubMed Central  Google Scholar 

  47. Moorhead WJ, Chu CC, Cuevas RA, Callahan J, Wong R, Regan C et al (2020) Dysregulation of FOXO1 (Forkhead Box O1 Protein) drives calcification in arterial calcification due to deficiency of CD73 and is present in peripheral artery disease. Arterioscler Thromb Vasc Biol 40(7):1680–1694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Narisawa S, Harmey D, Yadav MC, O’Neill WC, Hoylaerts MF, Millán JL (2007) Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification. J Bone Miner Res Off J Am Soc Bone Miner Res 22(11):1700–1710

    Article  CAS  Google Scholar 

  49. Ziegler SG, Ferreira CR, MacFarlane EG, Riddle RC, Tomlinson RE, Chew EY et al (2017) Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. Sci Transl Med. 9(393):eaal1669

    Article  PubMed  PubMed Central  Google Scholar 

  50. Li Q, Huang J, Pinkerton AB, Millan JL, van Zelst BD, Levine MA et al (2019) Inhibition of tissue-nonspecific alkaline phosphatase attenuates ectopic mineralization in the Abcc6-/- mouse model of PXE but not in the Enpp1 mutant mouse models of GACI. J Invest Dermatol 139(2):360–368

    Article  CAS  PubMed  Google Scholar 

  51. Warraich S, Bone DBJ, Quinonez D, Ii H, Choi D-S, Holdsworth DW et al (2013) Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans. J Bone Miner Res Off J Am Soc Bone Miner Res 28(5):1135–1149

    Article  CAS  Google Scholar 

  52. Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34(2–3):386–395

    Article  CAS  PubMed  Google Scholar 

  53. Villa-Bellosta R, Sorribas V (2008) Role of rat sodium/phosphate cotransporters in the cell membrane transport of arsenate. Toxicol Appl Pharmacol 232(1):125–134

    Article  CAS  PubMed  Google Scholar 

  54. Wagner CA, Hernando N, Forster IC, Biber J (2014) The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 466(1):139–153

    Article  CAS  PubMed  Google Scholar 

  55. Villa-Bellosta R, Bogaert YE, Levi M, Sorribas V (2007) Characterization of phosphate transport in rat vascular smooth muscle cells: implications for vascular calcification. Arterioscler Thromb Vasc Biol 27(5):1030–1036

    Article  CAS  PubMed  Google Scholar 

  56. Li X, Yang H-Y, Giachelli CM (2006) Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res 98(7):905–912

    Article  CAS  PubMed  Google Scholar 

  57. Crouthamel MH, Lau WL, Leaf EM, Chavkin NW, Wallingford MC, Peterson DF et al (2013) Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler Thromb Vasc Biol 33(11):2625–2632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang C, Li Y, Shi L, Ren J, Patti M, Wang T et al (2012) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44(3):254–256

    Article  CAS  PubMed  Google Scholar 

  59. Jensen N, Schrøder HD, Hejbøl EK, Füchtbauer E-M, de Oliveira JRM, Pedersen L (2013) Loss of function of Slc20a2 associated with familial idiopathic Basal Ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci MN 51(3):994–999

    Article  CAS  PubMed  Google Scholar 

  60. Ho AM, Johnson MD, Kingsley DM (2000) Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289(5477):265–270

    Article  CAS  PubMed  Google Scholar 

  61. Szeri F, Lundkvist S, Donnelly S, Engelke UFH, Rhee K, Williams CJ et al (2020) The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP. PLoS Genet 16(7):e1008884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nürnberg P, Thiele H, Chandler D, Höhne W, Cunningham ML, Ritter H et al (2001) Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet 28(1):37–41

    Article  PubMed  Google Scholar 

  63. Reichenberger E, Tiziani V, Watanabe S, Park L, Ueki Y, Santanna C et al (2001) Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet 68(6):1321–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gurley KA, Reimer RJ, Kingsley DM (2006) Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet 79(6):1017–1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Prosdocimo DA, Douglas DC, Romani AM, O’Neill WC, Dubyak GR (2009) Autocrine ATP release coupled to extracellular pyrophosphate accumulation in vascular smooth muscle cells. Am J Physiol Cell Physiol 296(4):C828-839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Costello JC, Rosenthal AK, Kurup IV, Masuda I, Medhora M, Ryan LM (2011) Parallel regulation of extracellular ATP and inorganic pyrophosphate: roles of growth factors, transduction modulators, and ANK. Connect Tissue Res 52(2):139–146

    Article  CAS  PubMed  Google Scholar 

  67. Zhang Y, Brown MA, Peach C, Russell G, Wordsworth BP (2007) Investigation of the role of ENPP1 and TNAP genes in chondrocalcinosis. Rheumatol Oxf Engl 46(4):586–589

    Article  CAS  Google Scholar 

  68. Addison WN, Azari F, Sørensen ES, Kaartinen MT, McKee MD (2007) Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem 282(21):15872–15883

    Article  CAS  PubMed  Google Scholar 

  69. Wang J, Tsui HW, Beier F, Pritzker KPH, Inman RD, Tsui FWL (2008) The ANKH ΔE490 mutation in calcium pyrophosphate dihydrate crystal deposition disease (CPPDD) affects tissue non-specific alkaline phosphatase (TNAP) activities. Open Rheumatol J 2:23–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang J, Tsui HW, Beier F, Tsui FWL (2009) The CPPDD-associated ANKH M48T mutation interrupts the interaction of ANKH with the sodium/phosphate cotransporter PiT-1. J Rheumatol j 36(6):1265–1272

    Article  Google Scholar 

  71. Couto AR, Zhang Y, Timms A, Bruges-Armas J, Sequeiros J, Brown MA (2012) Investigating ANKH and ENPP1 in Slovakian families with chondrocalcinosis. Rheumatol Int s 32(9):2745–2751

    Article  CAS  Google Scholar 

  72. Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M et al (2002) Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet 71(4):933–940

    Article  PubMed  PubMed Central  Google Scholar 

  73. Villa-Bellosta R, Egido J (2017) Phosphate, pyrophosphate, and vascular calcification: a question of balance. Eur Heart J 38(23):1801–1804

    CAS  PubMed  Google Scholar 

Download references

Funding

RV-B is a Senior Postdoctoral “Ramon y Cajal” Researcher (RYC2019-027920-I) supported by grants from the Spanish Ministerio de Ciencia e Innovacion (PID2020-113603RB-I00) and Spanish Society of Nephrology (SEN21-3315).

Author information

Authors and Affiliations

  1. Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Av Barcelona, Campus Vida, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain

    Ricardo Villa-Bellosta

  2. Department of Biochemistry and Molecular Biology, Universidade de Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain

    Ricardo Villa-Bellosta

Authors
  1. Ricardo Villa-Bellosta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo Villa-Bellosta.

Ethics declarations

Ethical approval

Ethical approval is not applicable to this article.

Informed consent

There are no human subjects in this article and informed consent is not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Villa-Bellosta, R. Role of the extracellular ATP/pyrophosphate metabolism cycle in vascular calcification. Purinergic Signalling 19, 345–352 (2023). https://doi.org/10.1007/s11302-022-09867-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11302-022-09867-1

Keywords

Search

Navigation