SpringerLink
Log in

NR2F1 overexpression alleviates trophoblast cell dysfunction by inhibiting GDF15/MAPK axis in preeclampsia

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE.

Graphical abstract

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 (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Availability of data and materials

The data of this study could be accessible from the corresponding author upon reasonable request.

References

  1. Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia-pathophysiology and clinical presentations: JACC state-of-the-art review. J Am Coll Cardiol. 2020;76(14):1690–702. https://doi.org/10.1016/j.jacc.2020.08.014.

    Article  CAS  PubMed  Google Scholar 

  2. Jim B, Karumanchi SA. Preeclampsia: pathogenesis, prevention, and long-term complications. Semin Nephrol. 2017;37(4):386–97. https://doi.org/10.1016/j.semnephrol.2017.05.011.

    Article  CAS  PubMed  Google Scholar 

  3. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res. 2019;124(7):1094–112. https://doi.org/10.1161/CIRCRESAHA.118.313276.

    Article  CAS  PubMed  Google Scholar 

  4. Gardikioti A, Venou TM, Gavriilaki E, Vetsiou E, Mavrikou I, Dinas K, et al. Molecular advances in preeclampsia and HELLP syndrome. Int J Mol Sci. 2022;23(7):3851. https://doi.org/10.3390/ijms23073851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Podymow T, August P. Hypertension in pregnancy. Adv Chronic Kidney Dis. 2007;14(2):178–90. https://doi.org/10.1053/j.ackd.2007.01.008.

    Article  PubMed  Google Scholar 

  6. Stevens DU, de Nobrega Teixeira JA, Spaanderman MEA, Bulten J, van Vugt JMG, Al-Nasiry S. Understanding decidual vasculopathy and the link to preeclampsia: a review. Placenta. 2020;97:95–100. https://doi.org/10.1016/j.placenta.2020.06.020.

    Article  CAS  PubMed  Google Scholar 

  7. Taysi S, Tascan AS, Ugur MG, Demir M. Radicals, oxidative/nitrosative stress and preeclampsia. Mini Rev Med Chem. 2019;19(3):178–93. https://doi.org/10.2174/1389557518666181015151350.

    Article  CAS  PubMed  Google Scholar 

  8. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The, “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193–201. https://doi.org/10.1016/j.ajog.2010.08.009.

    Article  PubMed  Google Scholar 

  9. Hardcastle TJ. Generalized empirical Bayesian methods for discovery of differential data in high-throughput biology. Bioinformatics. 2016;32(2):195–202. https://doi.org/10.1093/bioinformatics/btv569.

    Article  CAS  PubMed  Google Scholar 

  10. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308(5728):1592–4. https://doi.org/10.1126/science.1111726.

    Article  CAS  PubMed  Google Scholar 

  11. Romero R, Chaiworapongsa T. Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state. J Clin Invest. 2013;123(7):2775–7. https://doi.org/10.1172/JCI70431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. LaMarca B, Amaral LM, Harmon AC, Cornelius DC, Faulkner JL, Cunningham MW Jr. Placental ischemia and resultant phenotype in animal models of preeclampsia. Curr Hypertens Rep. 2016;18(5):38. https://doi.org/10.1007/s11906-016-0633-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366: l2381. https://doi.org/10.1136/bmj.l2381.

    Article  PubMed  Google Scholar 

  14. Carrasco-Wong I, Aguilera-Olguin M, Escalona-Rivano R, Chiarello DI, Barragan-Zuniga LJ, Sosa-Macias M, et al. Syncytiotrophoblast stress in early onset preeclampsia: the issues perpetuating the syndrome. Placenta. 2021;113:57–66. https://doi.org/10.1016/j.placenta.2021.05.002.

    Article  CAS  PubMed  Google Scholar 

  15. Mo HQ, Tian FJ, Li X, Zhang J, Ma XL, Zeng WH, et al. ANXA7 regulates trophoblast proliferation and apoptosis in preeclampsia. Am J Reprod Immunol. 2019;82(6): e13183. https://doi.org/10.1111/aji.13183.

    Article  PubMed  Google Scholar 

  16. Abbas Y, Turco MY, Burton GJ, Moffett A. Investigation of human trophoblast invasion in vitro. Hum Reprod Update. 2020;26(4):501–13. https://doi.org/10.1093/humupd/dmaa017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lala PK, Nandi P. Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: the role of decorin. Cell Adh Migr. 2016;10(1–2):111–25. https://doi.org/10.1080/19336918.2015.1106669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khalil BD, Sanchez R, Rahman T, Rodriguez-Tirado C, Moritsch S, Martinez AR, et al. An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy. J Exp Med. 2022;219(1): e20210836. https://doi.org/10.1084/jem.20210836.

    Article  CAS  PubMed  Google Scholar 

  19. Kim EJ, Kim JS, Lee S, Cheon I, Kim SR, Ko YH, et al. ZEB1-regulated lnc-Nr2f1 promotes the migration and invasion of lung adenocarcinoma cells. Cancer Lett. 2022;533: 215601. https://doi.org/10.1016/j.canlet.2022.215601.

    Article  CAS  PubMed  Google Scholar 

  20. Chadha M, Huang PH. Proteomic and metabolomic profiling in soft tissue sarcomas. Curr Treat Options Oncol. 2022;23(1):78–88. https://doi.org/10.1007/s11864-022-00947-3.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tocco C, Bertacchi M, Studer M. Structural and functional aspects of the neurodevelopmental gene NR2F1: from animal models to human pathology. Front Mol Neurosci. 2021;14: 767965. https://doi.org/10.3389/fnmol.2021.767965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bertacchi M, Parisot J, Studer M. The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease. Brain Res. 2019;1705:75–94. https://doi.org/10.1016/j.brainres.2018.04.024.

    Article  CAS  PubMed  Google Scholar 

  23. Schafer G, Wissmann C, Hertel J, Lunyak V, Hocker M. Regulation of vascular endothelial growth factor D by orphan receptors hepatocyte nuclear factor-4 alpha and chicken ovalbumin upstream promoter transcription factors 1 and 2. Cancer Res. 2008;68(2):457–66. https://doi.org/10.1158/0008-5472.CAN-07-5136.

    Article  CAS  PubMed  Google Scholar 

  24. Bukovsky A, Indrapichate K, Fujiwara H, Cekanova M, Ayala ME, Dominguez R, et al. Multiple luteinizing hormone receptor (LHR) protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer’s disease. Reprod Biol Endocrinol. 2003;1:46. https://doi.org/10.1186/1477-7827-1-46.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zhang Y, Dufau ML. Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. J Biol Chem. 2000;275(4):2763–70. https://doi.org/10.1074/jbc.275.4.2763.

    Article  CAS  PubMed  Google Scholar 

  26. ** H, Cai W, Yu D, Fan J, Liu Q, Yu J. Development of proliferative vitreoretinopathy is attenuated by chicken ovalbumin upstream promoter transcriptional factor 1 via inhibiting epithelial-mesenchymal transition. Discov Med. 2022;34(172):103–13.

    PubMed  Google Scholar 

  27. Gao XL, Zheng M, Wang HF, Dai LL, Yu XH, Yang X, et al. NR2F1 contributes to cancer cell dormancy, invasion and metastasis of salivary adenoid cystic carcinoma by activating CXCL12/CXCR4 pathway. BMC Cancer. 2019;19(1):743. https://doi.org/10.1186/s12885-019-5925-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rouault C, Clement K, Guesnon M, Henegar C, Charles MA, Heude B, et al. Transcriptomic signatures of villous cytotrophoblast and syncytiotrophoblast in term human placenta. Placenta. 2016;44:83–90. https://doi.org/10.1016/j.placenta.2016.06.001.

    Article  CAS  PubMed  Google Scholar 

  29. Leach RE, Kilburn BA, Petkova A, Romero R, Armant DR. Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor. Am J Obstet Gynecol. 2008;198(4):471 e1–7; discussion e7–8. https://doi.org/10.1016/j.ajog.2008.01.009.

  30. Zhang Z, Zhang L, Zhang L, Jia L, Wang P, Gao Y. Association of Wnt2 and sFRP4 expression in the third trimester placenta in women with severe preeclampsia. Reprod Sci. 2013;20(8):981–9. https://doi.org/10.1177/1933719112472740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fedorova L, Gatto-Weis C, Smaili S, Khurshid N, Shapiro JI, Malhotra D, et al. Down-regulation of the transcription factor snail in the placentas of patients with preeclampsia and in a rat model of preeclampsia. Reprod Biol Endocrinol. 2012;10:15. https://doi.org/10.1186/1477-7827-10-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kasture VV, Sundrani DP, Joshi SR. Maternal one carbon metabolism through increased oxidative stress and disturbed angiogenesis can influence placental apoptosis in preeclampsia. Life Sci. 2018;206:61–9. https://doi.org/10.1016/j.lfs.2018.05.029.

    Article  CAS  PubMed  Google Scholar 

  33. Hu H, Chen W, Tao Z, Li Z, He J, Peng Y, et al. Cyclosporin A alleviates trophoblast apoptosis and senescence by promoting autophagy in preeclampsia. Placenta. 2022;117:95–108. https://doi.org/10.1016/j.placenta.2021.11.003.

    Article  CAS  PubMed  Google Scholar 

  34. Park JI, Tsai SY, Tsai MJ. Molecular mechanism of chicken ovalbumin upstream promoter-transcription factor (COUP-TF) actions. Keio J Med. 2003;52(3):174–81. https://doi.org/10.2302/kjm.52.174.

    Article  CAS  PubMed  Google Scholar 

  35. Shibata H, Kurihara I, Kobayashi S, Yokota K, Suda N, Saito I, et al. Regulation of differential COUP-TF-coregulator interactions in adrenal cortical steroidogenesis. J Steroid Biochem Mol Biol. 2003;85(2–5):449–56. https://doi.org/10.1016/s0960-0760(03)00217-6.

    Article  CAS  PubMed  Google Scholar 

  36. Wang L, Yang Q. Circulating growth differentiation factor 15 and preeclampsia: a meta-analysis. Horm Metab Res. 2023;55(2):114–23. https://doi.org/10.1055/a-1956-2961.

    Article  CAS  PubMed  Google Scholar 

  37. Mumcu A. A different approach to the quantification of human seminal plasma metabolites using high-resolution NMR spectroscopy. J Pharm Biomed Anal. 2023;229: 115356. https://doi.org/10.1016/j.jpba.2023.115356.

    Article  CAS  PubMed  Google Scholar 

  38. Liao L, Liu M, Gao Y, Wei X, Yin Y, Gao L, et al. The long noncoding RNA TARID regulates the CXCL3/ERK/MAPK pathway in trophoblasts and is associated with preeclampsia. Reprod Biol Endocrinol. 2022;20(1):159. https://doi.org/10.1186/s12958-022-01036-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Qian X, Zhang Y. EZH2 enhances proliferation and migration of trophoblast cell lines by blocking GADD45A-mediated p38/MAPK signaling pathway. Bioengineered. 2022;13(5):12583–97. https://doi.org/10.1080/21655979.2022.2074620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guo KM, Li W, Wang ZH, He LC, Feng Y, Liu HS. Low-dose aspirin inhibits trophoblast cell apoptosis by activating the CREB/Bcl-2 pathway in pre-eclampsia. Cell Cycle. 2022;21(21):2223–38. https://doi.org/10.1080/15384101.2022.2092814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ridder A, Giorgione V, Khalil A, Thilaganathan B. Preeclampsia: the relationship between uterine artery blood flow and trophoblast function. Int J Mol Sci. 2019;20(13):3263. https://doi.org/10.3390/ijms20133263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Soleymanlou N, Jurisica I, Nevo O, Ietta F, Zhang X, Zamudio S, et al. Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab. 2005;90(7):4299–308. https://doi.org/10.1210/jc.2005-0078.

    Article  CAS  PubMed  Google Scholar 

  43. Fuenzalida B, Kallol S, Zaugg J, Mueller M, Mistry HD, Gutierrez J, et al. Primary human trophoblasts mimic the preeclampsia phenotype after acute hypoxia-reoxygenation insult. Cells. 2022;11(12):1898. https://doi.org/10.3390/cells11121898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Parisot J, Flore G, Bertacchi M, Studer M. COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal Cxcr4 expression. Development. 2017;144(11):2045–58. https://doi.org/10.1242/dev.139949.

    Article  CAS  PubMed  Google Scholar 

  45. Chen M, Wang J. Initiator caspases in apoptosis signaling pathways. Apoptosis. 2002;7(4):313–9. https://doi.org/10.1023/a:1016167228059.

    Article  CAS  PubMed  Google Scholar 

  46. Cohen GM. Caspases: the executioners of apoptosis. Biochem J. 1997;326(Pt 1):1–16. https://doi.org/10.1042/bj3260001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kasture V, Sundrani D, Randhir K, Wagh G, Joshi S. Placental apoptotic markers are associated with placental morphometry. Placenta. 2021;115:1–11. https://doi.org/10.1016/j.placenta.2021.08.051.

    Article  CAS  PubMed  Google Scholar 

  48. Shaker OG, Sadik NA. Pathogenesis of preeclampsia: Implications of apoptotic markers and oxidative stress. Hum Exp Toxicol. 2013;32(11):1170–8. https://doi.org/10.1177/0960327112472998.

    Article  CAS  PubMed  Google Scholar 

  49. Ruan X, Liu Y, Wang P, Liu L, Ma T, Xue Y, et al. RBMS3-induced circHECTD1 encoded a novel protein to suppress the vasculogenic mimicry formation in glioblastoma multiforme. Cell Death Dis. 2023;14(11):745. https://doi.org/10.1038/s41419-023-06269-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen J, Khalil RA. Matrix metalloproteinases in normal pregnancy and preeclampsia. Prog Mol Biol Transl Sci. 2017;148:87–165. https://doi.org/10.1016/bs.pmbts.2017.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Velicky P, Knofler M, Pollheimer J. Function and control of human invasive trophoblast subtypes: intrinsic vs. maternal control. Cell Adh Migr. 2016;10(1–2):154–62. https://doi.org/10.1080/19336918.2015.1089376.

    Article  PubMed  Google Scholar 

  52. Weiss G, Huppertz B, Siwetz M, Lang I, Moser G. Arterial endothelial cytokines guide extravillous trophoblast invasion towards spiral arteries; an in-vitro study with the trophoblast cell line ACH-3P and female non-uterine endothelial cells. Placenta. 2016;38:49–56. https://doi.org/10.1016/j.placenta.2015.12.010.

    Article  CAS  PubMed  Google Scholar 

  53. Pijnenborg R, Vercruysse L, Hanssens M. Fetal-maternal conflict, trophoblast invasion, preeclampsia, and the red queen. Hypertens Pregnancy. 2008;27(2):183–96. https://doi.org/10.1080/10641950701826711.

    Article  PubMed  Google Scholar 

  54. Nikolov A, Popovski N. Role of gelatinases MMP-2 and MMP-9 in healthy and complicated pregnancy and their future potential as preeclampsia biomarkers. Diagnostics (Basel). 2021;11(3):480. https://doi.org/10.3390/diagnostics11030480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Plaks V, Rinkenberger J, Dai J, Flannery M, Sund M, Kanasaki K, et al. Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction. Proc Natl Acad Sci U S A. 2013;110(27):11109–14. https://doi.org/10.1073/pnas.1309561110.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Liu Y, Chen S, Cai K, Zheng D, Zhu C, Li L, et al. Hypoxia-induced long noncoding RNA NR2F1-AS1 maintains pancreatic cancer proliferation, migration, and invasion by activating the NR2F1/AKT/mTOR axis. Cell Death Dis. 2022;13(3):232. https://doi.org/10.1038/s41419-022-04669-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cruickshank T, MacDonald TM, Walker SP, Keenan E, Dane K, Middleton A, et al. Circulating growth differentiation factor 15 is increased preceding preeclampsia diagnosis: implications as a disease biomarker. J Am Heart Assoc. 2021;10(16): e020302. https://doi.org/10.1161/JAHA.120.020302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wertaschnigg D, Rolnik DL, Nie G, Teoh SSY, Syngelaki A, da Silva CF, et al. Second- and third-trimester serum levels of growth-differentiation factor-15 in prediction of pre-eclampsia. Ultrasound Obstet Gynecol. 2020;56(6):879–84. https://doi.org/10.1002/uog.22070.

    Article  CAS  PubMed  Google Scholar 

  59. Zeng YT, Liu WF, Zheng PS, Li S. GDF15 deficiency hinders human trophoblast invasion to mediate pregnancy loss through downregulating Smad1/5 phosphorylation. iScience. 2023;26(10): 107902. https://doi.org/10.1016/j.isci.2023.107902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li S, Wang Y, Cao B, Wu Y, Ji L, Li YX, et al. Maturation of growth differentiation factor 15 in human placental trophoblast cells depends on the interaction with Matrix Metalloproteinase-26. J Clin Endocrinol Metab. 2014;99(11):E2277–87. https://doi.org/10.1210/jc.2014-1598.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang J, **g S, Zhang H, Zhang J, **e H, Feng L. Low-dose aspirin prevents LPS-induced preeclampsia-like phenotype via AQP-1 and the MAPK/ERK 1/2 pathway. Placenta. 2022;121:61–9. https://doi.org/10.1016/j.placenta.2022.03.007.

    Article  CAS  PubMed  Google Scholar 

  62. Wang Z, Zhao G, Zibrila AI, Li Y, Liu J, Feng W. Acetylcholine ameliorated hypoxia-induced oxidative stress and apoptosis in trophoblast cells via p38 MAPK/NF-kappaB pathway. Mol Hum Reprod. 2021;27(8): gaab045. https://doi.org/10.1093/molehr/gaab045.

    Article  CAS  PubMed  Google Scholar 

  63. Guo H, Zhao X, Li H, Liu K, Jiang H, Zeng X, et al. GDF15 promotes cardiac fibrosis and proliferation of cardiac fibroblasts via the MAPK/ERK1/2 pathway after irradiation in rats. Radiat Res. 2021;196(2):183–91. https://doi.org/10.1667/RADE-20-00206.1.

    Article  CAS  PubMed  Google Scholar 

  64. Tarfiei GA, Shadboorestan A, Montazeri H, Rahmanian N, Tavosi G, Ghahremani MH. GDF15 induced apoptosis and cytotoxicity in A549 cells depends on TGFBR2 expression. Cell Biochem Funct. 2019;37(5):320–30. https://doi.org/10.1002/cbf.3391.

    Article  CAS  PubMed  Google Scholar 

  65. Manikandan M, Abuelreich S, Elsafadi M, Alsalman H, Almalak H, Siyal A, et al. NR2F1 mediated down-regulation of osteoblast differentiation was rescued by bone morphogenetic protein-2 (BMP-2) in human MSC. Differentiation. 2018;104:36–41. https://doi.org/10.1016/j.diff.2018.10.003.

    Article  CAS  PubMed  Google Scholar 

  66. Liu W, Li S, Zhou Q, Fu Z, Liu P, Cao X, et al. 2, 2’, 4, 4’-tetrabromodiphenyl ether induces placental toxicity via activation of p38 MAPK signaling pathway in vivo and in vitro. Ecotoxicol Environ Saf. 2022;244: 114034. https://doi.org/10.1016/j.ecoenv.2022.114034.

    Article  CAS  PubMed  Google Scholar 

  67. Liu H, Wang F, Zhang Y, **ng Y, Wang Q. Exosomal microRNA-139-5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP-2 pathway via downregulation of protein tyrosine phosphatase. J Obstet Gynaecol Res. 2020;46(12):2561–72. https://doi.org/10.1111/jog.14495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. He GQ, Liu GY, Xu WM, Liao HJ, Liu XH, He GL. p57KIP2-mediated inhibition of human trophoblast apoptosis and promotion of invasion in vitro. Int J Mol Med. 2019;44(1):281–90. https://doi.org/10.3892/ijmm.2019.4175.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Obstetrics, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Ke Zhang, Hailing Zhang, Bing Wang, Shanshan Gao, Cai** Sun & Cong Jia

  2. Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, No. 2, **gba Road, Zhengzhou, Henan, People’s Republic of China

    **quan Cui

Authors
  1. Ke Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hailing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shanshan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cai** Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cong Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. **quan Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ke Zhang: data curation, formal analysis, validation, visualization, writing—original draft; Hailing Zhang: formal analysis, methodology, visualization, writing—original draft; Bing Wang: data curation, validation; Shanshan Gao: validation, writing—review and editing; Cai** Sun: validation, writing—review and editing; Cong Jia: writing—review and editing; **quan Cui: conceptualization, methodology, project administration, supervision, resources, writing—review and editing,

Corresponding author

Correspondence to **quan Cui.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethics approval

The study protocol was conformed to principles embodied in the Declaration of Helsinki and approved by the Ethics Committee of Zhengzhou University.

Informed consent

All participants provided informed consent.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, K., Zhang, H., Wang, B. et al. NR2F1 overexpression alleviates trophoblast cell dysfunction by inhibiting GDF15/MAPK axis in preeclampsia. Human Cell (2024). https://doi.org/10.1007/s13577-024-01095-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13577-024-01095-6

Keywords

Search

Navigation