Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cadmium-induced hypertension is associated with renal myosin light chain phosphatase inhibition via increased T697 phosphorylation and p44 mitogen-activated protein kinase levels

Hypertension Research volume 44, pages 941–954 (2021)Cite this article

Abstract

Dietary intake of the heavy metal cadmium (Cd2+) is implicated in hypertension, but potassium supplementation reportedly mitigates hypertension. This study aims to elucidate the hypertensive mechanism of Cd2+. Vascular reactivity and protein expression were assessed in Cd2+-exposed rats for 8 weeks to determine the calcium-handling effect of Cd2+ and the possible signaling pathways and mechanisms involved. Cd2+ induced hypertension in vivo by significantly (p < 0.001) elevating systolic blood pressure (160 ± 2 and 155 ± 1 vs 120 ± 1 mm Hg), diastolic blood pressure (119 ± 2 and 110 ± 1 vs 81 ± 1 mm Hg), and mean arterial pressure (133 ± 2 and 125 ± 1 vs 94 ± 1 mm Hg) (SBP, DBP, and MAP, respectively), while potassium supplementation protected against elevation of these parameters. The mechanism involved augmentation of the phosphorylation of renal myosin light chain phosphatase targeting subunit 1 (MYPT1) at threonine 697 (T697) (2.58 ± 0.36 vs 1 ± 0) and the expression of p44 mitogen-activated protein kinase (MAPK) (1.78 ± 0.20 vs 1 ± 0). While acetylcholine (ACh)-induced relaxation was unaffected, 5 mg/kg b.w. Cd2+ significantly (p < 0.001) attenuated phenylephrine (Phe)-induced contraction of the aorta, and 2.5 mg/kg b.w. Cd2+ significantly (p < 0.05) augmented sodium nitroprusside (SNP)-induced relaxation of the aorta. These results support the vital role of the kidney in regulating blood pressure changes after Cd2+ exposure, which may be a key drug target for hypertension management. Given the differential response to Cd2+, it is apparent that its hypertensive effects could be mediated by myosin light chain phosphatase (MLCP) inhibition via phosphorylation of renal MYPT1-T697 and p44 MAPK. Further investigation of small arteries and the Rho-kinase/MYPT1 interaction is recommended.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yoopan N, Watcharasit P, Wongsawatkul O, Piyachaturawat P, Satayavivad J. Attenuation of eNOS expression in cadmium-induced hypertensive rats. Toxicol Lett. 2008;176:157–61.

    Article  CAS  Google Scholar 

  2. Marchetti C. Role of calcium channels in heavy metal toxicity. ISRN Toxicol. 2013;2013:184360 https://doi.org/10.1155/2013/184360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abarikwu SO, Njoku R, Lawrence CJ, Charles IA, Ikewuchi JC. Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol. Pharm Biol. 2017;55:2161–9. https://doi.org/10.1080/13880209.2017.1387575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jackson WF. Potassium channels in regulation of vascular smooth muscle contraction and growth. Adv Pharm. 2017;78:89–144. https://doi.org/10.1016/bs.apha.2016.07.001.

    Article  CAS  Google Scholar 

  5. Poorolajal J, Zeraati F, Soltanian AR, Sheikh V, Hooshmand E, Maleki A. Oral potassium supplementation for management of essential hypertension: a meta-analysis of randomized controlled trials. PLoS One. 2017;12:e0174967–83. https://doi.org/10.1371/journal.pone.0174967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Salihi AB. Activation of inward rectifier potassium channels in high salt impairment of hydrogen sulphide-induced aortic relaxation in rats. Physiol Pharm. 2016;19:263–73.

    Google Scholar 

  7. Nesovic-Ostojic J, Cemerikic D, Dragovic S, Milovanovic A, Milovanovic J. Low micromolar concentrations of cadmium and mercury ions activate peritubular membrane K+ conductance in proximal tubular cells of frog kidney. Comp Biochem Physiol A Mol Integr Physiol. 2008;149:267–74. https://doi.org/10.1016/j.cbpa.2007.12.006.

    Article  CAS  PubMed  Google Scholar 

  8. Ruta LL, Popa VC, Nicolau I, Danet AF, Iordache V, Neagoe AD, et al. Calcium signalling mediates the response to cadmium toxicity in Saccharomyces cerevisiae cells. FEBS Lett. 2014;588:3202–12.

    Article  CAS  Google Scholar 

  9. Lopin KV, Thevenod F, Page JC, Jones SW. Cd2+ block and permeation of Cav3.1 (α-1G) T-type Ca2+ channels: candidate mechanism for Cd2+ influx. Mol Pharm. 2012;82:1183–93.

    Article  CAS  Google Scholar 

  10. Johnson RP, El-Yazbi AF, Takeya K, Walsh EJ, Walsh MP, Cole WC. Ca2+ sensitization via phosphorylation of myosin phosphatase targeting subunit at threonine-855 by Rho kinase contributes to the arterial myogenic response. J Physiol. 2009;587:2537–53.

    Article  CAS  Google Scholar 

  11. Kitazawa T, Somlyo AP. Modulation of Ca2+ sensitivity by agonists in smooth muscle. Adv Exp Med Biol. 1991;304:97–109. https://doi.org/10.1007/978-1-4684-6003-2_10.

    Article  CAS  PubMed  Google Scholar 

  12. Murahashi T, Fujita A. Kitazawa T. Ca2+ -induced Ca2+ desensitization of myosin light chain phosphorylation and contraction in phasic smooth muscle. Mol Cell Biochem. 1999;190:91–8.

    Article  CAS  Google Scholar 

  13. Ashraf MW. Levels of heavy metals in popular cigarette brands and exposure to these metals via smoking. Sci World J. 1–5, 2012. https://doi.org/10.1100/2012/729430.

  14. Almenara CCP, Broseghini-Filho GB, Vescovi MVA, Angeli JK, de Oliveira Faria T, Stefanon I, et al. Chronic cadmium treatment promotes oxidative stress and endothelial damage in isolated rat aorta. PLoS One. 2013;8:e68418.

    Article  CAS  Google Scholar 

  15. Nwokocha CR, Baker A, Douglas D, McCalla G, Nwokocha M, Brown PD. Apocynin ameliorates cadmium-induced hypertension through elevation of endothelium nitric oxide synthase. Cardiovasc Toxicol. 2013;13:357–63. https://doi.org/10.1007/s12012-013-9216-0.

    Article  CAS  PubMed  Google Scholar 

  16. Omogbai EK, Ozolua RI, Ebeigbe AB. Effects of potassium adaptation on blood pressure and pressor responses in normotensive and renal hypertensive Wistar rats. Methods Find Exp Clin Pharm. 2005;27:5–10. https://doi.org/10.1358/mf.2005.27.1.875430.

    Article  CAS  Google Scholar 

  17. Bautista-Ortega J, Stallone JN, Ruiz-Feria CA. Effects of arginine and antioxidant vitamins on pulmonary artery reactivity to phenylephrine in the broiler chicken. Poult Sci. 2013;92:1062–72. https://doi.org/10.3382/ps.2012-02472.

    Article  CAS  PubMed  Google Scholar 

  18. Angeli JK, Cruz Pereira CA, de Oliveira Faria T, Stefanon I, Padilha AS, Vassallo DV. Cadmium exposure induces vascular injury due to endothelial oxidative stress: the role of local angiotensin II and COX-2. Free Radic Biol Med. 2013;65:838–48.

    Article  CAS  Google Scholar 

  19. Ok SH, Lee HL, Yu J, Park J, Shin IW, Lee Y, et al. Lipid emulsion attenuates acetylcholine-induced relaxation in isolated rat aorta. Biomed Res Int. 2015;2015:871545–53. https://doi.org/10.1155/2015/871545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dang N, Pang S, Song H, An L, Ma X. Inactivation of mitogen-activated protein kinase signalling pathway reduces caspase-14 expression in impaired keratinocytes. Iran J Basic Med Sci. 2016;19:28–33.

    PubMed  PubMed Central  Google Scholar 

  21. Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.

    Article  CAS  Google Scholar 

  22. Schutte R, Nawrot T, Richart T, Thijs L, Roels HA, Van Bortel LM, et al. Arterial structure and function and environmental exposure to cadmium. Occup Environ Med. 2008;65:412–9. https://doi.org/10.1136/oem.2007.035576.

    Article  CAS  PubMed  Google Scholar 

  23. Assmann G, Cullen P, Evers T, Petzinna D, Schulte H. Importance of arterial pulse pressure as a predictor of coronary heart disease risk in PROCAM. Eur Heart J. 2005;26:2120–6. https://doi.org/10.1093/eurheartj/ehi467.

    Article  PubMed  Google Scholar 

  24. Reymond P, Westerhof N, Stergiopulos N. Systolic hypertension mechanisms: effect of global and local proximal aorta stiffening on pulse pressure. Ann Biomed Eng. 2012;40:742–9. https://doi.org/10.1007/s10439-011-0443-x.

    Article  PubMed  Google Scholar 

  25. Kim DH, Yoo JY, Lee SY, Kim YJ, Lee SR, Park SY. Effects of pulse pressure alterations on cardiac output measurements derived from analysis of arterial pressure waveform. Anesth Pain Med. 2016;11:280–4. https://doi.org/10.17085/apm.2016.11.3.280.

    Article  Google Scholar 

  26. Ozturk IM, Buyukakilli B, Balli E, Burak C, Gunes S, Semra Erdogan S. Determination of acute and chronic effects of cadmium on the cardiovascular system of rats. Toxicol Mech Methods. 2009;19:308–17.

    Article  CAS  Google Scholar 

  27. Crestani S, Webb RC, da Silva-Santos JE. High-salt intake augments the activity of the RhoA/ROCK pathway and reduces intracellular calcium in arteries from rats. Am J Hypertens. 2017;30:389–99. https://doi.org/10.1093/ajh/hpw20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cho YE, Ahn DE, Morgan KG, Lee YH. Enhanced contractility and myosin phosphorylation induced by Ca2+-independent MLCK activity in hypertensive rats. Cardiovasc Res. 2011;91:162–70. https://doi.org/10.1093/cvr/cvr043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mita M, Tanaka H, Yanagihara H, Nakagawa J, Hishinuma S, Sutherland C, et al. Membrane depolarization-induced RhoA/Rho-associated kinase activation and sustained contraction of rat caudal arterial smooth muscle involves genistein-sensitive tyrosine phosphorylation. J Smooth Muscle Res. 2013;49:26–45. https://doi.org/10.1540/jsmr.49.26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Seko T, Ito M, Kureishi Y, Okamoto R, Moriki N, Onishi K, et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res. 2003;92:411–8. https://doi.org/10.1161/01.RES.0000059987.90200.44.

    Article  CAS  PubMed  Google Scholar 

  31. Seok YM, Baek I, Kim YH, Jeong YS, Lee IJ, Shin DH, et al. Isoflavone attenuates vascular contraction through inhibition of the RhoA/Rho-kinase signalling pathway. J Pharm Exp Ther. 2008;326:991–8. https://doi.org/10.1124/jpet.108.138529.

    Article  CAS  Google Scholar 

  32. Seok YM, Azam MA, Okamoto Y, Sato A, Yoshioka K, Maeda M, et al. Enhanced Ca2+-dependent activation of phosphoinositide-3-kinase class IIα isoform-Rho axis in blood vessels of spontaneously hypertensive rats. Hypertension. 2010;56:934–41. https://doi.org/10.1161/HYPERTENSIONAHA.110.160853.

    Article  CAS  PubMed  Google Scholar 

  33. Kim S, Cheon HS, Kim SY, Juhnn YS, Kim YY. Cadmium induces neuronal cell death through reactive oxygen species activated by GADD153. BMC Cell Biol. 2013;14:4–12. https://doi.org/10.1186/1471-2121-14-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Adi PJ, Burra SP, Vataparti AR, Matcha B. Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats. Toxicol Rep. 2016;3:591–7. https://doi.org/10.1016/j.toxrep.2016.07.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Scott AJ, O’Dea KP, O’Callaghan D, Williams L, Dokpesi JO, Tatton L, et al. Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumour necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes. J Biol Chem. 2011;286:35466–76. https://doi.org/10.1074/jbc.M111.277434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Tanaka M, et al. Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. J Clin Invest. 1997;100:1813–21. https://doi.org/10.1172/JCI119709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nowak G, Clifton GL, Godwin ML, Bakajsova D. Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells. Am J Physiol Ren Physiol. 2006;291:F840–55. https://doi.org/10.1152/ajprenal.00219.2005.

    Article  CAS  Google Scholar 

  38. Parenti A, Cui XL, Hopfer U, Ziche M, Douglas JG. Activation of MAPKs in proximal tubule cells from spontaneously hypertensive and control Wistar-Kyoto rats. Hypertension. 2000;35:1160–6.

    Article  CAS  Google Scholar 

  39. Thind GS. Role of cadmium in human and experimental hypertension. J Air Pollut Control Assoc. 1972;22:267–70. https://doi.org/10.1080/00022470.1972.10469637.

    Article  CAS  PubMed  Google Scholar 

  40. Eum K-D, Lee M-S, Paek D. Cadmium in blood and hypertension. Sci Total Environ. 2008;407:147–53. https://doi.org/10.1016/j.scitotenv.2008.08.037.

    Article  CAS  PubMed  Google Scholar 

  41. Staessen JA, Kuznetsova T, Roels HA, Emelianov D, Fagard R. Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Public health and environmental exposure to cadmium study group. Am J Hypertens. 2000;13:146–56. https://doi.org/10.1016/s0895-7061(99)00187-9.

    Article  CAS  PubMed  Google Scholar 

  42. Satarug S, Nishijo M, Lasker JM, Edwards RJ, Moore MR. Kidney dysfunction and hypertension: role for cadmium, P450 and haem oxygenases? Tohoku J Exp Med. 208: 179–202. https://doi.org/10.1620/tjem.208.179.

  43. Broseghini-Filho GB, Almenara CC, Vescovi MV, Faria Tde O, Vassallo DV, Angeli JK, et al. Acute Cadmium exposure reduces the local angiotensin I converting enzyme activity and increases the tissue metal content. Biol Trace Elem Res. 2015;166:149–56. https://doi.org/10.1007/s12011-015-0250-6.

    Article  CAS  PubMed  Google Scholar 

  44. Nakagawa H, Nishijo M. Environmental cadmium exposure, hypertension and cardiovascular risk. J Cardiovasc Risk. 1996;3:11–7. https://doi.org/10.1177/174182679600300103.

    Article  CAS  PubMed  Google Scholar 

  45. Aoshima K. Itai-itai disease: renal tubular osteomalacia induced by environmental exposure to cadmium—historical review and perspectives. Soil Sci Plant Nutr. 2016;62:319–26. https://doi.org/10.1080/00380768.2016.1159116.

    Article  CAS  Google Scholar 

  46. Lalor GC, Rattray R, Williams N, Wright P. Cadmium levels in kidney and liver of Jamaicans at autopsy. West Indian Med J. 2004;53:76–80.

    CAS  PubMed  Google Scholar 

  47. Nishijo M, Nakagawa H, Suwazono Y, Nogawa K, Kido T. Causes of death in patients with Itai-itai disease suffering from severe chronic cadmium poisoning: a nested case-control analysis of a follow-up study in Japan. BMJ Open. 2017;7:e015694 https://doi.org/10.1136/bmjopen-2016-015694.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wright PR, Rattray R, Lalor G, Hanson R. Minimal health impact from exposure to diet-sourced cadmium on a population in central Jamaica. Environ Geochem Health. 2010;32:567–81. https://doi.org/10.1007/s10653-010-9318-6.

    Article  CAS  PubMed  Google Scholar 

  49. Shirran SL, Barran PE. The use of ESI-MS to probe the binding of divalent cations to calmodulin. J Am Soc Mass Spectrom. 2009;20:1159–71. https://doi.org/10.1016/j.jasms.2009.02.008.

    Article  CAS  PubMed  Google Scholar 

  50. Osol G, Brekke JF, McElroy-Yaggy K, Gokina NI. Myogenic tone, reactivity, and forced dilatation: a three-phase model of in vitro arterial myogenic behaviour. Am J Physiol Heart Circ Physiol. 2002;283:H2260–7. https://doi.org/10.1152/ajpheart.00634.2002.

    Article  CAS  PubMed  Google Scholar 

  51. Moreno-Domínguez A, El-Yazbi AF, Zhu HL, Colinas O, Zhong XZ, Walsh EJ, et al. Cytoskeletal reorganization evoked by Rho-associated kinase- and protein kinase C-catalyzed phosphorylation of cofilin and heat shock protein 27, respectively, contributes to myogenic constriction of rat cerebral arteries. J Biol Chem. 2014;289:20939–52. https://doi.org/10.1074/jbc.M114.553743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. El-Yazbi AF, Abd-Elrahman KS. ROK and arteriolar myogenic tone generation: molecular evidence in health and disease. Front Pharm. 2017;8:87. https://doi.org/10.3389/fphar.2017.00087.

    Article  CAS  Google Scholar 

  53. Moreno-Domínguez A, Colinas O, El-Yazbi A, Walsh EJ, Hill MA, Walsh MP, et al. Ca2+ sensitization due to myosin light chain phosphatase inhibition and cytoskeletal reorganization in the myogenic response of skeletal muscle resistance arteries. J Physiol. 2013;591:1235–50. https://doi.org/10.1113/jphysiol.2012.243576.

    Article  PubMed  Google Scholar 

  54. European Food Safety Authority (EFSA) Panel on Contaminants in the Food Chain (CONTAM). Scientific opinion on tolerable weekly intake for cadmium. EFSA J. 2011;9:1975–93. https://doi.org/10.2903/j.efsa.2011.1975.

    Article  CAS  Google Scholar 

  55. World Health Organization. Safety evaluation of certain contaminants in foods: cadmium-impact assessment of different maximum limits. Prepared by the Sixty-fourth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Food Additives Series 55. 2006;82:156–203.

  56. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for cadmium. ATSDR/U.S. Public Health Service, ATSDR/TP-88/08, Atlanta, US 1989.

  57. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Cadmium. Draft for public comment. US Department of Health and Human Services. Atlanta, US, 2008.

  58. Xu Q, Liu Y, Gorospe M, Udelsman R, Holbrook NJ. Acute hypertension activates mitogen-activated protein kinases in arterial wall. J Clin Invest. 1996;97:508–14.

    Article  CAS  Google Scholar 

  59. Chrissobolis S, Sobey CG. Evidence that Rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension: comparison with protein kinase C. Circ Res. 2001;88:774–9.

    Article  CAS  Google Scholar 

  60. González J, Valls N, Brito R, Rodrigo R. Essential hypertension and oxidative stress: new insights. World J Cardiol. 2014;6:353–66. https://doi.org/10.4330/wjc.v6.i6.353.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sutherland C, MacDonald JA, Walsh MP. Analysis of phosphorylation of the myosin-targeting subunit of myosin light chain phosphatase by Phos-tag SDS-PAGE. Am J Physiol Cell Physiol. 2016;310:C681–91. https://doi.org/10.1152/ajpcell.00327.2015.

    Article  PubMed  Google Scholar 

  62. Karaki H, Urakawa N, Kutsky P. Potassium-induced contraction in smooth muscle. Jpn J Smooth Muscle Res. 1984;20:427–44.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to express gratitude to Cindy Sutherland, Aaron Cull, Drs. Ryan Mills, Alejandro Moreno-Domínguez, Olaia Colinas, Emma Walsh, Hai-Lei Zhu, and Anthony Liwa for assistance with western blotting and members of Basic Medical Sciences, UWI, for technical assistance and help with the organ bath experiment.

Funding

This work was funded by grants obtained from the Mona Campus Committee for Research and Publications and Graduate Awards of the School for Graduate Studies and Research, University of the West Indies.

Author information

Authors and Affiliations

  1. Department of Basic Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, Kingston, Jamaica

    Garsha McCalla, Paul D. Brown & Chukwuemeka R. Nwokocha

  2. The Smooth Muscle Research Group, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    William C. Cole & Christine Campbell

Authors
  1. Garsha McCalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul D. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William C. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chukwuemeka R. Nwokocha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CRN conceptualized and designed the study and WCC, GM, and CC made some contributions to the methods. Material preparation and data collection and analysis were performed by GM, with western blot assistance from CC. The first draft of the paper was written by GM, and all authors commented on and edited subsequent versions of the paper. All authors contributed to the correction and finalization of the paper. GM and CRN acquired funding for the study. CRN and WCC provided resources for the study. CRN and PDB supervised the entire study. WCC supervised the western blot experiment.

Corresponding author

Correspondence to Garsha McCalla.

Ethics declarations

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCalla, G., Brown, P.D., Cole, W.C. et al. Cadmium-induced hypertension is associated with renal myosin light chain phosphatase inhibition via increased T697 phosphorylation and p44 mitogen-activated protein kinase levels. Hypertens Res 44, 941–954 (2021). https://doi.org/10.1038/s41440-021-00662-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-021-00662-w

Keywords

This article is cited by

Search

Advanced search

Quick links