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:

Magnesium sulfate prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization

Abstract

Preeclampsia is a complex disorder that is characterized by new onset hypertension and proteinuria at or after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and fetal morbidity and mortality. MgSO4 is commonly used to treat severe preeclampsia, but its mechanism of action is poorly understood, and investigations into the effects of MgSO4 during the postpartum period are lacking. In this study, timed-pregnant Sprague-Dawley rats received low-dose lipopolysaccharide (LPS) on gestational day 14 to induce preeclampsia. Maternal and fetal outcomes and the macrophage profile 1 week after delivery were explored. On postpartum day (PD) 7, the maternal systolic blood pressure and urinary protein level were significantly increased, the number of M1 macrophages was increased and the number of M2 macrophages was decreased in the maternal kidney and brain; the median duration of gestation, the number of live fetuses, and the fetal weight/placenta weight ratio were significantly decreased; and the percentage of growth-restricted pups and fetal mortality were significantly increased in preeclampsia rats compared to normal pregnant control rats. Prophylactic MgSO4 decreased blood pressure at PD7, improved pregnancy outcomes, and promoted the polarization of M2 macrophages in the kidney and of M2 microglia in the brain of preeclampsia rats. These findings confirm that the pathophysiology of preeclampsia involves the dysregulation of the inflammatory response and the activation of M1 macrophages in several target organs during pregnancy. MgSO4 prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization in the maternal kidney and brain.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

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

Similar content being viewed by others

References

  1. Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 2014;4:97–104. https://doi.org/10.1016/j.preghy.2014.02.001.

    Article  CAS  PubMed  Google Scholar 

  2. Black KD, Horowitz JA. Inflammatory markers and preeclampsia: a systematic review. Nurs Res. 2018;67:242–51. https://doi.org/10.1097/NNR.0000000000000285.

    Article  PubMed  Google Scholar 

  3. Tang J, He A, Li N, Chen X, Zhou X, Fan X, et al. Magnesium sulfate-mediated vascular relaxation and calcium channel activity in placental vessels different from nonplacental vessels. J Am Heart Assoc. 2018;7. https://doi.org/10.1161/JAHA.118.009896.

  4. Clayton AM, Shao Q, Paauw ND, Giambrone AB, Granger JP, Warrington JP. Postpartum increases in cerebral edema and inflammation in response to placental ischemia during pregnancy. Brain Behav Immun. 2018;70:376–89. https://doi.org/10.1016/j.bbi.2018.03.028.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive cytokines in women with preeclampsia. Am J Reprod Immunol. 1998;40:102–11. https://doi.org/10.1111/j.1600-0897.1998.tb00398.x.

    Article  CAS  PubMed  Google Scholar 

  6. Kara AE, Guney G, Tokmak A, Ozaksit G. The role of inflammatory markers hs-CRP, sialic acid, and IL-6 in the pathogenesis of preeclampsia and intrauterine growth restriction. Eur Cytokine Netw. 2019;30:29–33. https://doi.org/10.1684/ecn.2019.0423.

    Article  CAS  PubMed  Google Scholar 

  7. Kim S, Lee KS, Choi S, Kim J, Lee DK, Park M, et al. NF-kappaB-responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via down-regulation of endothelial nitric-oxide synthase. J Biol Chem. 2018;293:18989–9000. https://doi.org/10.1074/jbc.RA118.005197.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li X, Han X, Bao J, Liu Y, Ye A, Thakur M, et al. Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippocampus through the alpha7 nicotinic acetylcholine receptor. Brain Res. 2016;1642:487–96. https://doi.org/10.1016/j.brainres.2016.04.043.

    Article  CAS  PubMed  Google Scholar 

  9. Li X, Han X, Yang J, Bao J, Di X, Zhang G, et al. Magnesium sulfate provides neuroprotection in eclampsia-like seizure model by ameliorating neuroinflammation and brain edema. Mol Neurobiol. 2017;54:7938–48. https://doi.org/10.1007/s12035-016-0278-4.

    Article  CAS  PubMed  Google Scholar 

  10. Sibai BM. Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia. Am J Obstet Gynecol. 1990;162:1141–5. https://doi.org/10.1016/0002-9378(90)90002-o.

    Article  CAS  PubMed  Google Scholar 

  11. Celik Kavak E, Gulcu Bulmus F, Bulmus O, Kavak SB, Kocaman N. Magnesium: does it reduce ischemia/reperfusion injury in an adnexal torsion rat model?. Drug Des Dev Ther. 2018;12:409–15. https://doi.org/10.2147/DDDT.S157115.

    Article  Google Scholar 

  12. Li X, Liu H, Yang Y. Magnesium sulfate attenuates brain edema by lowering AQP4 expression and inhibits glia-mediated neuroinflammation in a rodent model of eclampsia. Behav Brain Res. 2019;364:403–12. https://doi.org/10.1016/j.bbr.2017.12.031.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang YH, He M, Wang Y, Liao AH. Modulators of the balance between M1 and M2 macrophages during pregnancy. Front Immunol. 2017;8:120. https://doi.org/10.3389/fimmu.2017.00120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schonkeren D, van der Hoorn ML, Khedoe P, Swings G, van Beelen E, Claas F, et al. Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies. Am J Pathol. 2011;178:709–17. https://doi.org/10.1016/j.ajpath.2010.10.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol. 1994;171:158–64. https://doi.org/10.1016/0002-9378(94)90463-4.

    Article  CAS  PubMed  Google Scholar 

  16. Orhan N, Ugur Yilmaz C, Ekizoglu O, Ahishali B, Arican N, Kucuk M, et al. The effects of superoxide dismutase mimetic MnTMPyP on the altered blood-brain barrier integrity in experimental preeclampsia with or without seizures in rats. Brain Res. 2014;1563:91–102. https://doi.org/10.1016/j.brainres.2014.03.029.

    Article  CAS  PubMed  Google Scholar 

  17. Wu WM, Suen JL, Lin BF, Chiang BL. Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL-lpr/lpr mice. Immunology. 2000;100:110–8. https://doi.org/10.1046/j.1365-2567.2000.00998.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. He J, Yuan G, Cheng F, Zhang J, Guo X. Mast Cell and M1 macrophage infiltration and local pro-inflammatory factors were attenuated with incretin-based therapies in obesity-related glomerulopathy. Metab Syndr Relat Disord. 2017;15:344–53. https://doi.org/10.1089/met.2017.0057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li Z, Zhang Y, Ying Ma J, Kapoun AM, Shao Q, Kerr I, et al. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007;50:686–92. https://doi.org/10.1161/HYPERTENSIONAHA.107.092098.

    Article  CAS  PubMed  Google Scholar 

  20. Lee CH, Wen ZH, Chang YC, Huang SY, Tang CC, Chen WF, et al. Intra-articular magnesium sulfate (MgSO4) reduces experimental osteoarthritis and nociception: association with attenuation of N-methyl-D-aspartate (NMDA) receptor subunit 1 phosphorylation and apoptosis in rat chondrocytes. Osteoarthr Cartil. 2009;17:1485–93. https://doi.org/10.1016/j.joca.2009.05.006.

    Article  CAS  Google Scholar 

  21. Gao F, Ding B, Zhou L, Gao X, Guo H, Xu H. Magnesium sulfate provides neuroprotection in lipopolysaccharide-activated primary microglia by inhibiting NF-kappaB pathway. J Surg Res. 2013;184:944–50. https://doi.org/10.1016/j.jss.2013.03.034.

    Article  CAS  PubMed  Google Scholar 

  22. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 134: fetal growth restriction. Obstet Gynecol.2013;121:1122–33. https://doi.org/10.1097/01.AOG.0000429658.85846.f9.

    Article  Google Scholar 

  23. Perucci LO, Correa MD, Dusse LM, Gomes KB, Sousa LP. Resolution of inflammation pathways in preeclampsia-a narrative review. Immunol Res. 2017;65:774–89. https://doi.org/10.1007/s12026-017-8921-3.

    Article  CAS  PubMed  Google Scholar 

  24. Shaw J, Tang Z, Schneider H, Salje K, Hansson SR, Guller S. Inflammatory processes are specifically enhanced in endothelial cells by placental-derived TNF-alpha: Implications in preeclampsia (PE). Placenta. 2016;43:1–8. https://doi.org/10.1016/j.placenta.2016.04.015.

    Article  CAS  PubMed  Google Scholar 

  25. Strevens H, Wide-Swensson D, Hansen A, Horn T, Ingemarsson I, Larsen S, et al. Glomerular endotheliosis in normal pregnancy and pre-eclampsia. BJOG. 2003;110:831–6.

    Article  CAS  Google Scholar 

  26. McKinney D, Boyd H, Langager A, Oswald M, Pfister A, Warshak CR. The impact of fetal growth restriction on latency in the setting of expectant management of preeclampsia. Am J Obstet Gynecol. 2016;214:395 e1–7. https://doi.org/10.1016/j.ajog.2015.12.050.

    Article  Google Scholar 

  27. Schiessl B. Inflammatory response in preeclampsia. Mol Asp Med. 2007;28:210–9. https://doi.org/10.1016/j.mam.2007.04.004.

    Article  CAS  Google Scholar 

  28. Kemp PA, Gardiner SM, March JE, Rubin PC, Bennett T. Assessment of the effects of endothelin-1 and magnesium sulphate on regional blood flows in conscious rats, by the coloured microsphere reference technique. Br J Pharmacol. 1999;126:621–6. https://doi.org/10.1038/sj.bjp.0702342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vishnyakova P, Elchaninov A, Fatkhudinov T, Sukhikh G. Role of the monocyte-macrophage system in normal pregnancy and preeclampsia. Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms20153695.

  30. Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387:999–1011. https://doi.org/10.1016/S0140-6736(15)00070-7.

    Article  PubMed  Google Scholar 

  31. Boyle AK, Rinaldi SF, Norman JE, Stock SJ. Preterm birth: Inflammation, fetal injury and treatment strategies. J Reprod Immunol. 2017;119:62–6. https://doi.org/10.1016/j.jri.2016.11.008.

    Article  PubMed  Google Scholar 

  32. Schutten JC, Joris PJ, Mensink RP, Danel RM, Goorman F, Heiner-Fokkema MR, et al. Effects of magnesium citrate, magnesium oxide and magnesium sulfate supplementation on arterial stiffness in healthy overweight individuals: a study protocol for a randomized controlled trial. Trials. 2019;20:295. https://doi.org/10.1186/s13063-019-3414-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huang Q, Liu L, Hu B, Di X, Brennecke SP, Liu H. Decreased seizure threshold in an eclampsia-like model induced in pregnant rats with lipopolysaccharide and pentylenetetrazol treatments. PLoS ONE 2014;9:e89333. https://doi.org/10.1371/journal.pone.0089333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yang H, Kim TH, Lee GS, Hong EJ, Jeung EB. Comparing the expression patterns of placental magnesium/phosphorus-transporting channels between healthy and preeclamptic pregnancies. Mol Reprod Dev. 2014;81:851–60. https://doi.org/10.1002/mrd.22353.

    Article  CAS  PubMed  Google Scholar 

  35. Vigil-De Gracia P, Ramirez R, Duran Y, Quintero A. Magnesium sulfate for 6 vs 24 h post delivery in patients who received magnesium sulfate for less than 8 h before birth: a randomized clinical trial. BMC Pregnancy Childbirth. 2017;17:241. https://doi.org/10.1186/s12884-017-1424-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sugimoto J, Romani AM, Valentin-Torres AM, Luciano AA, Ramirez Kitchen CM, Funderburg N, et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol. 2012;188:6338–46. https://doi.org/10.4049/jimmunol.1101765.

    Article  CAS  PubMed  Google Scholar 

  37. Burwick RM, Togioka BM, Speranza RJ, Gaffney JE, Roberts VHJ, Frias AE, et al. Assessment of blood-brain barrier integrity and neuroinflammation in preeclampsia. Am J Obstet Gynecol. 2019;221:269. e1–8. https://doi.org/10.1016/j.ajog.2019.06.024.

    Article  CAS  Google Scholar 

  38. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95:1–46. https://doi.org/10.1152/physrev.00012.2014.

    Article  CAS  PubMed  Google Scholar 

  39. Kreepala C, Luangphiphat W, Villarroel A, Kitporntheranunt M, Wattanavaekin K, Piyajarawong T. Effect of magnesium on glomerular filtration rate and recovery of hypertension in women with severe preeclampsia. Nephron. 2018;138:35–41. https://doi.org/10.1159/000481463.

    Article  CAS  PubMed  Google Scholar 

  40. Suzuki-Kakisaka H, Sugimoto J, Tetarbe M, Romani AM, Ramirez Kitchen CM, Bernstein HB. Magnesium sulfate increases intracellular magnesium reducing inflammatory cytokine release in neonates. Am J Reprod Immunol. 2013;70:213–20. https://doi.org/10.1111/aji.12118.

    Article  CAS  PubMed  Google Scholar 

  41. Rochelson B, Dowling O, Schwartz N, Metz CN. Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway. J Reprod Immunol. 2007;73:101–7. https://doi.org/10.1016/j.jri.2006.06.004.

    Article  CAS  PubMed  Google Scholar 

  42. Bosio PM, McKenna PJ, Conroy R, O’Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol. 1999;94:978–84. https://doi.org/10.1016/s0029-7844(99)00430-5.

    Article  CAS  PubMed  Google Scholar 

  43. Paauw ND, Joles JA, Spradley FT, Bakrania B, Zsengeller ZK, Franx A, et al. Exposure to placental ischemia impairs postpartum maternal renal and cardiac function in rats. Am J Physiol Regul Integr Comp Physiol. 2017;312:R664–70. https://doi.org/10.1152/ajpregu.00510.2016.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tomimatsu T, Mimura K, Endo M, Kumasawa K, Kimura T. Pathophysiology of preeclampsia: an angiogenic imbalance and long-lasting systemic vascular dysfunction. Hypertens Res. 2017;40:305–10. https://doi.org/10.1038/hr.2016.152.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by a grant from the National Natural Science Foundation of China (No. 81801477) and the Ph.D. Programs Foundation of the First Affiliated Hospital of Anhui Medical University in China.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yuanyuan Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Li, X., Li, L., Tao, L. et al. Magnesium sulfate prophylaxis attenuates the postpartum effects of preeclampsia by promoting M2 macrophage polarization. Hypertens Res 44, 13–22 (2021). https://doi.org/10.1038/s41440-020-0511-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-020-0511-4

Keywords

This article is cited by

Search

Quick links