Epigenetic aspects of the pathogenesis of preeclampsia

Kan N.E., Mirzabekova D.D., Tyutyunnik V.L., Krasnyi A.M.

Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia
Preeclampsia is a serious pregnancy complication that is a leading cause of maternal and perinatal morbidity and mortality. Of great interest is the study of new approaches to preventing, predicting, and treating this syndrome; however, it is difficult without understanding the basics of pathogenesis. The paper considers modern ideas about the mechanisms of preeclampsia. Fundamental significance is attached to the activation of the immune system; the cells of both innate and adaptive immunity are assumed to play a key role. It is known that epigenetic mechanisms, such as DNA methylation and the action of non-coding RNAs (ncRNAs), regulate many genes, including those involved in inflammation and immune response, and can serve as prognostic biomarkers and therapeutic targets in preeclampsia.
Conclusion: The study of etiopathogenesis can become the basis for revealing the mechanism of this pregnancy complication, which directly facilitates the search for new markers for the early diagnosis of preeclampsia.

Keywords

preeclampsia
innate immunity
monocyte-macrophage response
epigenetic mechanisms

References

  1. Wilkerson R.G., Ogunbodede A.C. Hypertensive disorders of pregnancy. Emerg. Med. Clin. North Am. 2019; 37(2): 301-16. https://dx.doi.org/10.1016/j.emc.2019.01.008.
  2. Rana S., Lemoine E., Granger J.P., Karumanchi S.A. Preeclampsia: pathophysiology, challenges, and perspectives. Circ. Res. 2019; 124(7): 1094-112. https://dx.doi.org/10.1161/CIRCRESAHA.118.313276. Erratum in: Circ. Res. 2020; 126 (1): e8.
  3. Министерство здравоохранения Российской Федерации. Преэклампсия. Эклампсия. Отеки, протеинурия и гипертензивные расстройства во время беременности, в родах и послеродовом периоде. Федеральные клинические рекомендации (протокол лечения). М.; 2021. 81с. [Preeclampsia. Eclampsia. Edema, proteinuria and hypertensive disorders during pregnancy, childbirth and the postpartum period: Federal clinical guidelines (treatment protocol). Moscow, 2021. 81 p. (in Russian)].
  4. Abalos E., Cuesta C., Grosso A.L., Chou D., Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur. J. Obstet. Gynecol. Reprod. Biol. 2013; 170(1): 1-7. https://dx.doi.org/10.1016/j.ejogrb.2013.05.005.
  5. Игнатко И.В., Флорова В.С., Кузнецов А.С., Кузина Е.Ю. Роль биохимических маркеров в стратификации риска развития преэклампсии: взгляд клинициста. Архив акушерства и гинекологии им. В.Ф. Снегирева. 2017; 4(4): 181-6. https://dx.doi.org/10.18821/2313-8726-2017-4-4-181-186. [Ignatko IV, Florova VS, Kuznetsov AC, Kuzina EY. The role of biochemical markers in the risk stratification for development of preeclampsia: the clinician’s view. V.F. Snegirev Archives of Obstetrics and Gynecology. 2017; 4 (4): 181-186.(in Russian)]. https://dx.doi.org/10.18821/2313-8726-2017-4-4-181-186.
  6. Abalos E., Cuesta C., Carroli G., Qureshi Z., Widmer M., Vogel J.P., Souza J.P.;WHO Multicountry Survey on Maternal and Newborn Health Research Network. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health. BJOG. 2014; 121(Suppl. 1): 14-24. https://dx.doi.org/10.1111/1471-0528.12629.
  7. Савельева Г.М., Шалина Р.И., Коноплянников А.Г., Симухина М.А. Преэклампсия и эклампсия: новые подходы к диагностике и оценке степени тяжести. Акушерство и гинекология: новости, мнения, обучение. 2018; 6(4): 25-30. https://dx.doi.org/10.24411/2303-9698-2018-14002. [Savel’eva G.M., Shalina R.I., Konoplyannikov A.G., Simuhina M.A.
  8. Preeclampsia and eclampsia: new approaches in diagnosis and evaluation of severity. Akusherstvo i ginekologiya: novosti, mneniya, obuchenie. 2018; 6 (4): 25-30. (in Russian)]. https://dx.doi.org/10.24411/2303-9698-2018-14002.
  9. Kalisch-Smith J.I., Simmons D.G., Dickinson H., Moritz K.M. Review: Sexual dimorphism in the formation, function and adaptation of the placenta. Placenta. 2017; 54: 10-6. https://dx.doi.org/10.1016/j.placenta.2016.12.008.
  10. Павлов О.В., Сельков С.А. Плацентарные макрофаги. Морфофункциональные характеристики и роль в гестационном процессе. СПб.: Эко-Вектор; 2018. 223с. [Pavlov O.V., Selkov S.A.Placental macrophages. Morphofunctional characteristics and role in the gestational process. – St. Petersburg: Eco-Vector, 2018. – 223 p.(in Russian)].
  11. Magatti M., Masserdotti A., Cargnoni A., Papait A., Stefani F.R., Silini A.R., Parolini O. The role of B cells in PE pathophysiology: a potential target for perinatal cell-based therapy? Int. J. Mol. Sci. 2021; 22(7): 3405.https://dx.doi.org/10.3390/ijms22073405.
  12. Lima J., Cambridge G., Vilas-Boas A., Martins C., Borrego L.M., Leandro M. Serum markers of B-cell activation in pregnancy during late gestation, delivery, and the postpartum period. Am. J. Reprod. Immunol. 2019; 81(3): e13090. https://dx.doi.org/10.1111/aji.13090.
  13. Gharesi-Fard B., Mobasher-Nejad F., Nasri F. The expression of T-helper associated transcription factors and cytokine genes in pre-eclampsia. Iran. J. Immunol. 2016; 13(4): 296-308.
  14. Zolfaghari M.A., Arefnezhad R., Parhizkar F., Hejazi M.S., Motavalli Khiavi F.,Mahmoodpoor A., Yousefi M. T lymphocytes and preeclampsia: The potential role of T-cell subsets and related MicroRNAs in the pathogenesis of preeclampsia. Am. J. Reprod. Immunol. 2021; 86(5): e13475.https://dx.doi.org/10.1111/aji.13475.
  15. Nagayama S., Shirasuna K., Nagayama M., Nishimura S., Takahashi M., Matsubara S., Ohkuchi A. Decreased circulating levels of plasmacytoid dendritic cells in women with early-onset preeclampsia. J. Reprod. Immunol. 2020; 141: 103170. https://dx.doi.org/10.1016/j.jri.2020.103170.
  16. Chistiakov D.A., Sobenin I.A., Orekhov A.N., Bobryshev Y.V. Myeloid dendritic cells: development, functions, and role in atherosclerotic inflammation. Immunobiology. 2015; 220(6): 833-44. https://dx.doi.org/10.1016/j.imbio.2014.12.010.
  17. Gilliet M., Cao W., Liu Y.J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 2008; 8(8):594-606. https://dx.doi.org/10.1038/nri2358.
  18. Perdiguero E.G., Geissmann F. The development and maintenance of resident macrophages. Nat. Immunol. 2016; 17(1): 2-8. https://dx.doi.org/10.1038/ni.3341.
  19. Martinez F.O., Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6: 13. https://dx.doi.org/10.12703/P6-13.
  20. Okizaki S., Ito Y., Hosono K., Oba K., Ohkubo H., Amano H., Shichiri M., Majima M. Suppressed recruitment of alternatively activated macrophages reduces TGF-β1 and impairs wound healing in streptozotocin-induced diabetic mice. Biomed. Pharmacother. 2015; 70: 317-25. https://dx.doi.org/10.1016/j.biopha.2014.10.020.
  21. Nunes P.R., Romão-Veiga M., Peraçoli J.C., Araujo Costa R.A., de Oliveira L.G., Borges V.T.M., Peraçoli M.T. Downregulation of CD163 in monocytes and its soluble form in the plasma is associated with a pro-inflammatory profile in pregnant women with preeclampsia. Immunol. Res. 2019; 67(2-3): 194-201. https://dx.doi.org/10.1007/s12026-019-09078-8.
  22. Ziegler-Heitbrock L. Monocyte subsets in man and other species. Cell. Immunol. 2014; 289(1-2): 135-9. https://dx.doi.org/10.1016/j.cellimm.2014.03.019.
  23. Mildner A., Marinkovic G., Jung S. Murine monocytes: origins, subsets, fates, and functions. Microbiol. Spectr. 2016; 4(5). https://dx.doi.org/10.1128/microbiolspec.MCHD-0033-2016.
  24. Борис Д.А., Волгина Н.Е., Красный А.М., Тютюнник В.Л., Кан Н.Е. Прогнозирование преэклампсии по содержанию CD16-негативных моноцитов. Акушерство и гинекология. 2019; 7: 49-55. https://dx.doi.org/10.18565/aig.2019.7.49-55. [Boris D.A., Volgina N.E., Krasnyi A.M., Tyutyunnik V.L., Kan N.E. Prediction of preeclampsia on the couts of CD-16 negative monocytes Akusherstvo i ginekologiya / Obstetrics and Gynecology, 2019; 7: 49-55. (in Russian)]. https://dx.doi.org/10.18565/aig.2019.7.49-55.
  25. Melgert B.N., Spaans F., Borghuis T., Klok P.A., Groen B., Bolt A. et al. Pregnancy and preeclampsia affect monocyte subsets in humans and rats. PLoS One. 2012; 7(9): e45229. https://dx.doi.org/10.1371/journal.pone.0045229.
  26. Tang M.X., Zhang Y.H., Hu L., Kwak-Kim J., Liao A.H. CD14++ CD16+ HLA-DR+ Monocytes in peripheral blood are quantitatively correlated with the severity of pre-eclampsia. Am. J. Reprod. Immunol. 2015; 74(2): 116-22. https://dx.doi.org/10.1111/aji.12389.
  27. Alahakoon T.I., Medbury H., Williams H., Fewings N., Wang X.M., Lee V.W. Characterization of fetal monocytes in preeclampsia and fetal growth restriction. J. Perinat. Med. 2019; 47(4): 434-8. https://dx.doi.org/10.1515/jpm-2018-0286.
  28. Yeap W.H., Wong K.L., Shimasaki N., Teo E.C., Quek J.K., Yong H.X. et al. CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes. Sci. Rep. 2016; 6: 34310. https://dx.doi.org/10.1038/srep34310.
  29. Karapetian А.О., Baev О.R., Sadekova А.А., Krasnyi А.М., Sukhikh G.T. Cell-free foetal DNA as a useful marker for preeclampsia prediction. Reprod. Sci. 2021; 28(5): 1563-9. https://dx.doi.org/10.1007/s43032-021-00466-w.
  30. Peng Y., Luo G., Zhou J., Wang X., Hu J., Cui Y. et al. CD86 is an activation receptor for NK cell cytotoxicity against tumor cells. PLoS One. 2013; 8 (12): e83913. https://dx.doi.org/10.1371/journal.pone.0083913.
  31. Horton H.M., Bernett M.J., Peipp M., Pong E., Karki S., Chu S.Y. et al. Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. Blood. 2010; 116(16): 3004-12. https://dx.doi.org/10.1182/blood-2010-01-265280.
  32. Bradley C.A. CD24 – a novel ‘don’t eat me’ signal. Nat. Rev. Cancer. 2019; 19(10): 541. https://dx.doi.org/10.1038/s41568-019-0193-x.
  33. Hayat S.M.G., Bianconi V., Pirro M., Jaafari M.R., Hatamipour M., Sahebkar A.CD47: role in the immune system and application to cancer therapy. Cell. Oncol. (Dordr.). 2020; 43(1): 19-30. https://dx.doi.org/10.1007/s13402-019-00469-5.
  34. Barkal A.A., Brewer R.E., Markovic M., Kowarsky M., Barkal S.A., Zaro B.W. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature. 2019; 572(7769): 392-6. https://dx.doi.org/10.1038/s41586-019-1456-0.
  35. Apicella C., Ruano C.S.M., Méhats C., Miralles F., Vaiman D. The role of epigenetics in placental development and the etiology of preeclampsia. Int. J. Mol. Sci. 2019; 20(11): 2837. https://dx.doi.org/10.3390/ijms20112837.
  36. Борис Д.А., Красный А.М., Куревлев С.В., Садекова А.А., Кан Н.Е., Тютюнник В.Л. Метилирование генов TLR2 и ICR IGF2/H19 в плаценте и плазме крови при преэклампсии. Акушерство и гинекология. 2020; 7: 93-8. https://dx.doi.org/10.18565/aig.2020.7.93-98. [Boris DA, Krasnyi AM, Kurevlev SV, Sadekova AA, Kan NE, Tyutyunnik VL. DNA methylation genes of TLR2 and ICR IGF2/H19 in placneta and blood plasma with preeclampsia. Akusherstvo i ginekologiya / Obstetrics and Gynecology, 2020; 7: 93-98. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.7.93-98.
  37. Almomani S.N., Alsaleh A.A., Weeks R.J., Chatterjee A., Day R.C., Honda I. et al. Identification and validation of DNA methylation changes in pre-eclampsia. Placenta. 2021; 110: 16-23. https://dx.doi.org/10.1016/j.placenta.2021.05.005.
  38. Wang W., Min L., Qiu X., Wu X., Liu C., Ma J. et al. Biological function of long non-coding RNA (LncRNA) Xist. Front. Cell Dev. Biol. 2021; 9: 645647. https://dx.doi.org/10.3389/fcell.2021.645647.
  39. Huang T., Chen W., Liu J., Gu N., Zhang R. Genome-wide identification of mRNA 5-methylcytosine in mammals. Nat. Struct. Mol. Biol. 2019; 26(5): 380-8. https://dx.doi.org/10.1038/s41594-019-0218-x.
  40. Hombach S., Kretz M. Non-coding RNAs: classification, biology and functioning. Adv. Exp. Med. Biol. 2016; 937: 3-17. https://dx.doi.org/10.1007/978-3-319-42059-2_1.
  41. Rokni M., Salimi S., Sohrabi T., Asghari S., Teimoori B., Saravani M. Association between miRNA-152 polymorphism and risk of preeclampsia susceptibility. Arch. Gynecol. Obstet. 2019; 299(2): 475-80. https://dx.doi.org/10.1007/s00404-018-4979-y.
  42. Hong F., Li Y., Xu Y. Decreased placental miR-126 expression and vascular endothelial growth factor levels in patients with pre-eclampsia. J. Int. Med. Res. 2014; 42(6): 1243-51. https://dx.doi.org/10.1177/0300060514540627.
  43. Gong R.Q., Nuh A.M., Cao H.S., Ma M. Roles of exosomes-derived lncRNAs in preeclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 2021; 263: 132-8.https://dx.doi.org/10.1016/j.ejogrb.2021.06.015.
  44. Luo X., Li X. Long non-coding RNAs serve as diagnostic biomarkers of preeclampsia and modulate migration and invasiveness of trophoblast cells. Med. Sci. Monit. 2018; 24: 84-91. https://dx.doi.org/10.12659/msm.907808.
  45. Михайлова В.А., Овчинникова О.М., Зайнулина М.С., Соколов Д.И., Сельков С.А. Выявление микрочастиц лейкоцитарного происхождения в периферической крови при физиологической беременности и при преэклампсии. Бюллетень экспериментальной биологии и медицины. 2014; 157(6): 721-6. [Mikhailova V.A., Ovchinnikova O.M., Zainulina M.S.,
  46. Sokolov D.I., Selkov S.A. Detection of microparticles of leukocyte origin in peripheral blood during physiological pregnancy and preeclampsia. Bull. Exp. Biol. Med. 2014; 157(6): 721-6. (in Russian)].
  47. Wang Z., Zhao G., Zeng M., Feng W., Liu J. Overview of extracellular vesicles in the pathogenesis of preeclampsia†. Biol. Reprod. 2021; 105(1): 32-9.https://dx.doi.org/10.1093/biolre/ioab060.
  48. Кореневский А.В., Березкина М.Э., Герт Т.Н., Синявин С.А., Сельков С.А., Соколов Д.И. Экспрессия поверхностных молекул и функциональные характеристики эндотелиальных клеток: влияние белковых фракций лизата микровезикул естественных киллеров в системе in vitro. Медицинская иммунология. 2022; 24(3): 463-80. https://dx.doi.org/10.15789/1563-0625-PAF-2376. [Korenevsky A.V., Berezkina M.E., Gert T.N., Sinyavin S.A., Selkov S.A., Sokolov D.I. Phenotypic and functional characteristics of endothelial cells: the in vitro effects of protein fractions from the lysate of natural killer-derived microvesicles. Medical Immunology (in Russian)]. 2022; 24(3): 463-480. https://dx.doi.org/10.15789/1563-0625-PAF-2376.
  49. Matsubara K., Matsubara Y., Uchikura Y., Sugiyama T. Pathophysiology of preeclampsia: the role of exosomes. Int. J. Mol. Sci. 2021; 22(5): 2572.https://dx.doi.org/10.3390/ijms22052572.
  50. Göhner C., Fledderus J., Fitzgerald J.S., Schleußner E., Markert U.R., Scherjon S.A., Plösch T., Faas M.M. Syncytiotrophoblast exosomes guide monocyte maturation and activation of monocytes and granulocytes. Placenta. 2015; 36: A47-8. https://dx.doi.org/10.1016/j.placenta.2015.07.329.
  51. Salomon C., Guanzon D., Scholz-Romero K., Longo S., Correa P., Illanes S.E., Rice G.E. Placental exosomes as early biomarker of preeclampsia: potential role of exosomal MicroRNAs across gestation. J. Clin. Endocrinol. Metab. 2017; 102(9): 3182-94. https://dx.doi.org/10.1210/jc.2017-00672.
  52. Li X., Song Y., Liu F., Liu D., Miao H., Ren J. et al. Long non-coding RNA MALAT1 promotes proliferation, angiogenesis, and immunosuppressive properties of mesenchymal stem cells by inducing VEGF and IDO. J. Cell. Biochem. 2017; 118(9): 2780-91. https://dx.doi.org/10.1002/jcb.25927.
  53. Zhao Z., Sun W., Guo Z., Zhang J., Yu H., Liu B. Mechanisms of lncRNA/microRNA interactions in angiogenesis. Life Sci. 2020; 254: 116900.https://dx.doi.org/10.1016/j.lfs.2019.116900.
  54. Yan T., Liu Y., Cui K., Hu B., Wang F., Zou L. MicroRNA-126 regulates EPCs function: implications for a role of miR-126 in preeclampsia. J. Cell. Biochem. 2013; 114(9): 2148-59. https://dx.doi.org/10.1002/jcb.24563.

Received 23.08.2022

Accepted 14.09.2022

About the Authors

Natalia E. Kan, Professor, MD, PhD; Deputy Director of Science; Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, +7(926)220-86-55, kan-med@mail.ru, Researcher ID: B-2370-2015, SPIN-код: 5378-8437, Authors ID: 624900,
Scopus Author ID: 57008835600, https://orcid.org/0000-0001-5087-5946, 117997, Russia, Moscow, Ac. Oparina str., 4.
Dzhamilia D. Mirzabekova, graduate student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health
of Russia, +7(906)110-51-13, +7(920)984-94-07, Jamilya1705@yandex.ru, https://orcid.org/0000-0002-2391-3334, 117997, Russia, Moscow, Ac. Oparina str., 4.
Victor L. Tyutyunnik, Professor, MD, PhD, Leading Researcher of Research and Development Service, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, +7(903)969-50-41, tioutiounnik@mail.ru, Researcher ID: B-2364-2015,
SPIN-код: 1963-1359, Authors ID: 213217, Scopus Author ID: 56190621500, https://orcid.org/0000-0002-5830-5099, 117997, Russia, Moscow, Ac. Oparina str., 4.
Aleksey M. Krasnyi, PhD, Head of the Cytology Laboratory, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology,
Ministry of Health of Russia, +7(495)438-22-72, alexred@list.ru, 117997, Russia, Moscow, Ac. Oparina str., 4.

Authors’ contributions: Kan N.E., Mirzabekova D.D., Tyutyunnik V.L., Krasnyi A.M. – concept and development of the design of the investigation, obtaining the data to be analyzed, collection of publications, processing and analyzing the material on the topic, writing the text of the manuscript, editing the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has not been sponsored.
For citation: Kan N.E., Mirzabekova D.D., Tyutyunnik V.L., Krasnyi A.M.
Epigenetic aspects of the pathogenesis of preeclampsia.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 12: 5-10 (in Russian)
https://dx.doi.org/10.18565/aig.2022.198

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.