New technologies in solving the problems of preeclampsia

DOI

https://dx.doi.org/10.18565/aig.2022.10.5-13

Nikitina N.A., Sidorova I.S., Ageev M.B., Timofeev S.A., Kiryanova M.A., Morozova E.A.
Obstetrics and Gynecology Department No. 1, N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of the Russian Federation, Moscow, Russia

This review deals with the current state of the problem of preeclampsia in obstetrics. It is emphasized that hypertensive disorders and preeclampsia still retain their positions among the leading causes of maternal death in Russia in the presence of a progressive increase in the incidence of severe preeclampsia. The high percentage of preventable and potential preventable cases of maternal death due to preeclampsia (72.5% in 2020) suggests that there is a need for further improvement of the management strategy for these patients, as well as a deeper study of the pathophysiological mechanisms responsible for the development of this pregnancy complication. The paper emphasizes that the concept of failure of cytotrophoblast invasion as a cause of preeclampsia is currently in doubt. Taking into account the modern principles of personalized medicine, there is a need for innovative large-scale, high-throughput, unbiased researches. These requirements are met by the latest methods in systems biology, in particular, the so-called omics technologies (genomics, epigenetics, transcriptomics, proteomics, and metabolomics). The paper presents studies published in the largest databases on the use of omics technologies in the study of preeclampsia.
Conclusion: A comprehensive study of the structure of a genome, as well as many ways of implementing genetic information (a systematic multi-omic design) will be able to gain a complete idea of the physiological and pathological processes, including preeclampsia.

maternal mortality

hypertensive disorders

pregnancy

preeclampsia

transcriptomics

proteomics

transcriptome

proteome

microRNA

placental liquid biopsy

Full text (in Russian)

Естественное движение населения в Российской Федерации за 2020 год. Федеральная служба государственной статистики. Статистический бюллетень. М.; 2021. Доступно по: https://gks.ru/bgd/regl/b20_106/Main.htm [Natural population movement in the Russian Federation for 2020. Federal State Statistics Service. Statistical bulletin. Moscow; 2021. Available at:https://gks.ru/bgd/regl/b20_106/Main.htm (in Russian)].
Филиппов О.С., Гусева Е.В. Материнская смертность в Российской Федерации в 2019 г. Проблемы репродукции. 2020; 26(6-2): 8-26. [Filippov O.S., Guseva E.V. Maternal mortality in the Russian Federation in 2019. Russian Journal of Human Reproduction. 2020; 26(6 2): 8-26.(in Russian)]. https://dx.doi.org/10.17116/repro2020260628.
Филиппов О.С., Гусева Е.В. Материнская смертность в Российской Федерации в 2020 году: первый год пандемии COVID-19. Проблемы репродукции. 2022; 28(1): 8-28. [Filippov O.S., Guseva E.V. Maternal mortality in the Russian Federation in 2020: the first year of the pandemic. Russian Journal of Human Reproduction. 2022; 28(1): 8-28. (in Russian)]. https://dx.doi.org/10.17116/repro2022280118.
Villar J., Ariff S., Gunier R.B., Thiruvengadam R., Rauch S., Kholin A. et al. Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: The INTERCOVID Multinational Cohort Study. JAMA Pediatr. 2021; 175(8): 817-26. https://dx.doi.org/10.1001/jamapediatrics.2021.1050.
Huppertz B. The critical role of abnormal trophoblast development in the etiology of preeclampsia. Curr. Pharm. Biotechnol. 2018; 19(10): 771-80. https://dx.doi.org/10.2174/1389201019666180427110547.
Verlohren S., Melchiorre K., Khalil A., Thilaganathan B. Uterine artery Doppler, birth weight and timing of onset of pre-eclampsia: providing insights into the dual etiology of late-onset pre-eclampsia. Ultrasound Obstet. Gynecol. 2014; 44(3): 293-8. https://dx.doi.org/10.1002/uog.13310.
Demers S., Boutin A., Gasse C., Drouin O., Girard M., Bujold E. First-trimester uterine artery Doppler for the prediction of preeclampsia in nulliparous women: The Great Obstetrical Syndrome Study. Am. J. Perinatol. 2019; 36(9): 930-5. https://dx.doi.org/10.1055/s-0038-1675209.
Harris L.K., Benagiano M., D'Elios M.M., Brosens I., Benagiano G. Placental bed research: II. Functional and immunological investigations of the placental bed. Am. J. Obstet. Gynecol. 2019; 221(5): 457-69. https:/dx./doi.org/10.1016/j.ajog.2019.07.010.
Choudhury R.H., Dunk C.E., Lye S.J., Aplin J.D., Harris L.K.,Jones R.L. Extravillous trophoblast and endothelial cell crosstalk mediates leukocyte infiltration to the early remodeling decidual spiral arteriole wall. J. Immunol. 2017; 198(10): 4115-28. https://dx.doi.org/10.4049/jimmunol.1601175.
McGinnis R., Steinthorsdottir V., Williams N.O., Thorleifsson G., Shooter S.,Hjartardottir S. et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nat. Genet. 2017; 49(8): 1255-60.https://dx.doi.org/10.1038/ng.3895.
Zhao L., Bracken M.B., DeWan A.T. Genome-wide association study of pre-eclampsia detects novel maternal single nucleotide polymorphisms and copy-number variants in subsets of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study cohort. Ann. Hum. Genet. 2013; 77(4): 277-87. https://dx.doi.org/10.1111/ahg.12021.
Ashraf U.M., Hall D.L., Rawls A.Z., Alexander B.T. Epigenetic processes during preeclampsia and effects on fetal development and chronic health. Clin. Sci. (London). 2021; 135(19): 2307-27. https://dx.doi.org/10.1042/CS20190070.
Osunkalu V.O., Taiwo I.A., Makwe C.C., Abiola A.A., Quao R.A., Anorlu R.I. Epigenetic Modification in Methylene Tetrahydrofolate Reductase (MTHFR) gene of women with pre-eclampsia. J. Obstet. Gynaecol. India. 2021; 71(1): 52-7. https://dx.doi.org/10.1007/s13224-020-01374-w.
Yeung K.R., Chiu C.L., Pidsley R., Makris A., Hennessy A., Lind J.M. DNA methylation profiles in preeclampsia and healthy control placentas. Am. J. Physiol. Heart Circ. Physiol. 2016; 310(10): H1295-303.https://dx.doi.org/10.1152/ajpheart.00958.2015.
Bahado-Singh R.O., Syngelaki A., Akolekar R., Mandal R., Bjondahl T.C., Han B. et al. Validation of metabolomic models for prediction of early-onset preeclampsia. Am. J. Obstet. Gynecol. 2015; 213(4): 530.e1-530.e10.https://dx.doi.org/10.1016/j.ajog.2015.06.044.
Benny P.A., Alakwaa F.M., Schlueter R.J., Lassiter C.B., Garmire L.X. A review of omics approaches to study preeclampsia. Placenta. 2020; 92: 17-27.https://dx.doi.org/10.1016/j.placenta.2020.01.008.
Yong H.E.J., Chan S.Y. Current approaches and developments in transcript profiling of the human placenta. Hum. Reprod. Update. 2020; 26(6): 799-840. https://dx.doi.org/10.1093/humupd/dmaa028.
Szilagyi A., Gelencser Z., Romero R., Xu Y., Kiraly P., Demeter A. et al. Placenta-specific genes, their regulation during villous trophoblast differentiation and dysregulation in preterm preeclampsia. Int. J. Mol. Sci. 2020; 21(2): 628.https://dx.doi.org/10.3390/ijms21020628.
Leavey K., Benton S.J., Grynspan D., Bainbridge S.A., Morgen E.K., Cox B.J. Gene markers of normal villous maturation and their expression in placentas with maturational pathology. Placenta. 2017; 58: 52-9. https://dx.doi.org/10.1016/j.placenta.2017.08.005.
Lim Y.C., Li J., Ni Y., Liang Q., Zhang J., Yeo G.S.H. et al. A complex association between DNA methylation and gene expression in human placenta at first and third trimesters. PLoS One. 2017; 12(7): e0181155. https://dx.doi.org/10.1371/journal.pone.0181155.
Wang B., Wang P., Parobchak N., Treff N., Tao X., Wang J. et al. Integrated RNA-seq and ChIP-seq analysis reveals a feed-forward loop regulating H3K9ac and key labor drivers in human placenta. Placenta. 2019; 76: 40-50.https://dx.doi.org/10.1016/j.placenta.2019.01.010.
Kaartokallio T., Cervera A., Kyllönen A., Laivuori K., Kere J., Laivuori H. et al. Gene expression profiling of pre-eclamptic placentae by RNA sequencing. Sci. Rep. 2015; 5: 14107. https://dx.doi.org/10.1038/srep14107.
Guo C., Cai P., Jin L., Sha Q., Yu Q., Zhang W. et al. Single-cell profilingof the human decidual immune microenvironment in patients with recurrent pregnancy loss. Cell Discov. 2021; 7(1): 1. https://dx.doi.org/10.1038/s41421-020-00236-z.
Zhou W., Wang H., Yang Y., Guo F., Yu B., Su Z. Trophoblast cell subtypes and dysfunction in the placenta of individuals with preeclampsia revealed by single-cell RNA sequencing. Mol. Cells. 2022; 45(5): 317-28.https://dx.doi.org/10.14348/molcells.2021.0211.
Vishnyakova P., Poltavets A., Nikitina M., Muminova K., Potapova A.,Vtorushina V. et al. Preeclampsia: inflammatory signature of decidual cells in early manifestation of disease. Placenta. 2021; 104: 277-83.https://doi.org/10.1016/j.placenta.2021.01.011.
Moufarrej M.N., Vorperian S.K., Wong R.J., Campos A.A., Quaintance C.C., Sit R.V. et al. Early prediction of preeclampsia in pregnancy with cell-free RNA. Nature. 2022; 602(7898): 689-94. https://dx.doi.org/10.1038/s41586-022-04410-z.
Condrat C.E., Varlas V.N., Duică F., Antoniadis P., Danila C.A., Cretoiu D. et al. Pregnancy-related extracellular vesicles revisited. Int. J. Mol. Sci. 2021; 22(8): 3904. https://dx.doi.org/10.3390/ijms22083904.
Забанова Е.А., Кузнецова Н.Б., Шкурат Т.П., Бутенко Е.В. МикроРНК регуляция в генезе задержки роста плода. Акушерство и гинекология. 2019; 12: 5-11. [Zabanova E.A., Kuznetsova N.B., Skurat T.P., Butenko E.V. MicroRNA regulation in the genesis of fetal growth restriction. Obstetrics and Gynecology. 2019; 12: 5-11. (in Russian)]. https://dx.doi.org/10.18565/aig.2019.12.5-11.
Ermini L., Ausman J., Melland-Smith M., Yeganeh B., Rolfo A., Litvack M.L. et al. A single sphingomyelin species promotes exosomal release of endoglin into the maternal circulation in preeclampsia. Sci. Rep. 2017; 7(1): 12172.https://dx.doi.org/10.1038/s41598-017-12491-4.
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.
Tominaga N., Yoshioka Y., Ochiya T. A novel platform for cancer therapy using extracellular vesicles. Adv. Drug Deliv. Rev. 2015; 95: 50-5. https://dx.doi.org/10.1016/j.addr.2015.10.002.
Lai R.C., Yeo R.W., Lim S.K. Mesenchymal stem cell exosomes. Semin. Cell Dev. Biol. 2015; 40: 82-8. https://dx.doi.org/10.1016/j.semcdb.2015.03.001.
Teng X., Chen L., Chen W., Yang J., Yang Z., Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell. Physiol. Biochem. 2015; 37(6): 2415-24. https://dx.doi.org/10.1159/000438594.
Wang D., Na Q., Song G.Y., Wang L. Human umbilical cord mesenchymal stem cell-derived exosome-mediated transfer of microRNA-133b boosts trophoblast cell proliferation, migration and invasion in preeclampsia by restricting SGK1. Cell Cycle (Georgetown, Tex.) . 2020; 19(15): 1869-83. https://dx.doi.org/10.1080/15384101.2020.1769394.
Salomon C., Guanzon D., Scholz-Romero K., Longo S., Correa P., Illanes S.E. et al. 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.
Cai M., Kolluru G.K., Ahmed A. Small molecule, big prospects: MicroRNA in pregnancy and its complications. J. Pregnancy. 2017; 2017: 6972732.https://dx.doi.org/10.1155/2017/6972732.
Kolkova Z., Holubekova V., Grendar M., Nachajova M., Zubor P., Pribulova T. et al. Association of circulating miRNA expression with preeclampsia, its onset, and severity. Diagnostics (Basel). 2021; 11(3): 476. https://dx.doi.org/10.3390/diagnostics11030476.
Selvaraj S., Lakshmanan G., Kalimuthu K., Sekar D. Role of microRNAs and their involvement in preeclampsia. Epigenomics. 2020; 12(20): 1765-7.https://dx.doi.org/10.2217/epi-2020-0281.
Akgör U., Ayaz L., Çayan F. Expression levels of maternal plasma microRNAs in preeclamptic pregnancies. J. Obstet. Gynaecol. 2021; 41(6): 910-4.https://dx.doi.org/10.1080/01443615.2020.1820465.
Murakami Y., Miura K., Sato S., Higashijima A., Hasegawa Y., Miura S. et al. Reference values for circulating pregnancy-associated microRNAs in maternal plasma and their clinical usefulness in uncomplicated pregnancy and hypertensive disorder of pregnancy. J. Obstet. Gynaecol. Res. 2018; 44(5):840-51. https://dx.doi.org/10.1111/jog.13610.
Hromadnikova I., Kotlabova K., Krofta L. Cardiovascular disease-associated MicroRNA dysregulation during the first trimester of gestation in women with chronic hypertension and normotensive women subsequently developing gestational hypertension or preeclampsia with or without fetal growth restriction. Biomedicines. 2022; 10(2): 256. https://dx.doi.org/10.3390/biomedicines10020256.
Kim S., Lee K.S., Choi S., Kim J., Lee D.K., Park M. et al. NF-κB-responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via down-regulation of endothelial nitric-oxide synthase. J. Biol. Chem. 2018; 293(49): 18989-9000. https://dx.doi.org/10.1074/jbc.RA118.005197.
Li Q., Han Y., Xu P., Yin L., Si Y., Zhang C. et al. Elevated microRNA-125b inhibits cytotrophoblast invasion and impairs endothelial cell function in preeclampsia. Cell Death Discov. 2020; 6: 35. https://dx.doi.org/10.1038/s41420-020-0269-0.
Wu L., Song W.Y., Xie Y., Hu L.L., Hou X.M., Wang R. et al. miR-181a-5p suppresses invasion and migration of HTR-8/SVneo cells by directly targeting IGF2BP2. Cell Death Dis. 2018; 9(2): 16. https://dx.doi.org/10.1038/s41419-017-0045-0.
He A., Zhou Y., Wei Y., Li R. Potential protein biomarkers for preeclampsia. Cureus. 2020; 12(6): e8925. https://dx.doi.org/10.7759/cureus.8925.
Tarca A.L., Romero R., Benshalom-Tirosh N., Than N.G., Gudicha D.W., Done B. et al. The prediction of early preeclampsia: Results from a longitudinal proteomics study. PLoS One. 2019; 14(6): e0217273. https://dx.doi.org/10.1371/journal.pone.0217273.
Kawasaki K., Kondoh E., Chigusa Y., Kawamura Y., Mogami H., Takeda S. et al. Metabolomic profiles of placenta in preeclampsia. Hypertension. 2019; 73(3): 671-9. https://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12389.
Jaremek A., Jeyarajah M.J., Jaju Bhattad G., Renaud S.J. Omics approaches to study formation and function of human placental syncytiotrophoblast. Front. Cell Dev. Biol. 2021; 9: 674162. https://dx.doi.org/10.3389/fcell.2021.674162.
Lu X., Wang R., Zhu C., Wang H., Lin H.Y., Gu Y. et al. Fine-tuned and cell-cycle-restricted expression of fusogenic protein syncytin-2 maintains functional placental syncytia. Cell Rep. 2017; 21(5): 1150-9. https://dx.doi.org/10.1016/j.celrep.2017.10.019.
Baines K.J., Renaud S.J. Transcription factors that regulate trophoblast development and function. Prog. Mol. Biol. Transl. Sci. 2017; 145: 39-88. https://dx.doi.org/10.1016/bs.pmbts.2016.12.003.
Knöfler M., Haider S., Saleh L., Pollheimer J., Gamage T.K.J.B., James J. Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell. Mol. Life Sci. 2019; 76(18): 3479-96. https://dx.doi.org/10.1007/s00018-019-03104-6.
Knott J.G., Paul S. Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation. Reproduction. 2014; 148(6):R121-36. https://dx.doi.org/10.1530/REP-14-0072.

Received 14.06.2022

Accepted 20.07.2022

Natalya A. Nikitina, Dr. Med. Sci., Professor at the Department of Obstetrics and Gynecology No. 1, I.M. Sechenov First Moscow State Medical University,
Institute of Clinical Medicine named after N.V. Sklifosovsky, +7(916)940-39-34, natnikitina@list.ru, https://orcid.org/0000-0001-8659-9963,
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2.
Iraida S. Sidorova, Academician of the RAS, Dr. Med. Sci., Professor at the Department of Obstetrics and Gynecology No. 1, I.M. Sechenov First Moscow State Medical University, Institute of Clinical Medicine named after N.V. Sklifosovsky, +7(910)438-90-87, sidorovais@yandex.ru, https://orcid.org/0000-0003-2209-8662,
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2.
Mikhail B. Ageev, PhD, Associate Professor at the Department of Obstetrics and Gynecology No. 1, I.M. Sechenov First Moscow State Medical University,
Institute of Clinical Medicine named after N.V. Sklifosovsky, +7(916)510-90-27, mikhaageev@yandex.ru, https://orcid.org/0000-0002-6603-804X,
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2.
Sergej A. Timofeev, Teaching Assistant at the Department of Obstetrics and Gynecology No. 1, I.M. Sechenov First Moscow State Medical University,
Institute of Clinical Medicine named after N.V. Sklifosovsky, +7(916)681-31-19, satimofeev30@gmail.com, https://orcid.org/0000-0001-7380-9255,
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2.
Marina A. Kiryanova, graduate student at the Department of Obstetrics and Gynecology No. 1, I.M. Sechenov First Moscow State Medical University,
Institute of Clinical Medicine named after N.V. Sklifosovsky, +7(918)334-37-74, kiryanova.marina8@mail.ru, https://orcid.org/0000-0001-6950-5283,
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2.
Ekaterina A. Morozova, graduate student at the Department of Obstetrics and Gynecology No. 1, I.M. Sechenov First Moscow State Medical University,
Institute of Clinical Medicine named after N.V. Sklifosovsky, +7(916)123-23-30, drstrelnikova@mail.ru, https://orcid.org/0000-0002-1670-9044,
119991, Russia, Moscow, Trubetskaya str. 8, bld. 2.
Corresponding author: Marina A. Kiryanova, kiryanova.marina8@mail.ru

Authors' contributions: Sidorova I.S., Nikitina N.A. – concept and design of the investigation, editing; Timofeev S.A., Morozova E.A. – material collection and processing; Nikitina N.A., Ageev M.B., Kiryanova M.A. – writing the text.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has been conducted without additional funding.
For citation: Nikitina N.A., Sidorova I.S., Ageev M.B., Timofeev S.A., Kiryanova M.A.,
Morozova E.A. New technologies in solving the problems of preeclampsia.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 10: 5-13 (in Russian)
https://dx.doi.org/10.18565/aig.2022.10.5-13

New technologies in solving the problems of preeclampsia

Nikitina N.A., Sidorova I.S., Ageev M.B., Timofeev S.A., Kiryanova M.A., Morozova E.A.

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