Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells

Yan Shen; Qingyu Cui; Li Xiao; Lifeng Wang; Qianqian Li; Ruihong Zhang; Zhaowen Chen; Jianmin Niu

doi:10.1515/jpm-2022-0565

Article

Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells

Yan Shen , Qingyu Cui , Li Xiao , Lifeng Wang , Qianqian Li , Ruihong Zhang , Zhaowen Chen and Jianmin Niu

Published/Copyright: September 12, 2023

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Perinatal Medicine Volume 52 Issue 1

Abstract

Objectives

Preeclampsia (PE) is a disease specific to pregnancy that causes 9–10 % of maternal deaths. Early-onset PE (<34 weeks’ gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a’s role in trophoblast cells.

Methods

Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation.

Results

In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=−0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis.

Conclusions

Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction.

Keywords: early-onset preeclampsia; Wnt7a; GPR124; placenta; trophoblast

Corresponding author: Jianmin Niu, Department of Obstetrics, Shenzhen Maternity and Child Healthcare Hospital, Cheeloo College of Medicine, Shandong University, Shenzhen, Guangdong, P.R. China, Phone: +86 10 8288 9999, Fax: +86 10 8288 9999, E-mail: niujianminshd@163.com

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 81830041

Funding source: High-level talents incubation plan scientific research project of Maternal and Child Health Care Hospital of Shandong Provincial, Cheeloo College of Medicine, Shandong University

Award Identifier / Grant number: 2022RS06

Research ethics: Approval was granted by the Ethics Committee of Maternal and Child Health Care Hospital of Shandong Provincial, Cheeloo College of Medicine, Shandong University on 28.09.2020.
Informed consent: Informed consent was obtained from all individuals included in this study.
Author contributions: Jianmin Niu led the development of the concept and design of the study. Yan Shen performed the research and wrote the manuscript. Qingyu Cui was responsible for data analysis. Li Xiao, Lifeng Wang assisted with some of the experiments, Zhaowen Chen, Qianqian Li, Ruihong Zhang collected the samples and recruited the study participants. All authors have reviewed and approved the manuscript.
Competing interests: The authors state no conflict of interest.
Research funding: The research was funded by National Natural Science Foundation of China (81830041); High-level talents incubation plan scientific research project of Maternal and Child Health Care Hospital of Shandong Provincial, Cheeloo College of Medicine, Shandong University (2022RS06).

References

1. Wilkerson, RG, Ogunbodede, AC. Hypertensive disorders of pregnancy. Emerg Med Clin North Am 2019;37:301–16. https://doi.org/10.1016/j.emc.2019.01.008.Search in Google Scholar PubMed

2. Tranquilli, AL. Early and late-onset pre-eclampsia. Pregnancy Hypertens 2014;4:241–7. https://doi.org/10.1016/j.preghy.2014.04.007.Search in Google Scholar PubMed

3. Guo, F, Zhang, B, Yang, H, Fu, Y, Wang, Y, Huang, J, et al.. Systemic transcriptome comparison between early- and late-onset pre-eclampsia shows distinct pathology and novel biomarkers. Cell Prolif 2021;54:e12968. https://doi.org/10.1111/cpr.12968.Search in Google Scholar PubMed PubMed Central

4. Mula, R, Meler, E, Albaiges, G, Rodriguez, I. Strategies for the prediction of late preeclampsia. J Matern Fetal Neonatal Med 2019;32:3729–33. https://doi.org/10.1080/14767058.2018.1471592.Search in Google Scholar PubMed

5. Sato, Y. Endovascular trophoblast and spiral artery remodeling. Mol Cell Endocrinol 2020;503:110699. https://doi.org/10.1016/j.mce.2019.110699.Search in Google Scholar PubMed

6. Staff, AC. The two-stage placental model of preeclampsia: an update. J Reprod Immunol 2019;134–135:1–10. https://doi.org/10.1016/j.jri.2019.07.004.Search in Google Scholar PubMed

7. Tomimatsu, T, Mimura, K, Matsuzaki, S, Endo, M, Kumasawa, K, Kimura, T. Preeclampsia: maternal systemic vascular disorder caused by generalized endothelial dysfunction due to placental antiangiogenic factors. Int J Mol Sci 2019;20:4246. https://doi.org/10.3390/ijms20174246.Search in Google Scholar PubMed PubMed Central

8. El-Sayed, AAF. Preeclampsia: a review of the pathogenesis and possible management strategies based on its pathophysiological derangements. Taiwan J Obstet Gynecol 2017;56:593–8. https://doi.org/10.1016/j.tjog.2017.08.004.Search in Google Scholar PubMed

9. Correa, PJ, Palmeiro, Y, Soto, MJ, Ugarte, C, Illanes, SE. Etiopathogenesis, prediction, and prevention of preeclampsia. Hypertens Pregnancy 2016;35:280–94. https://doi.org/10.1080/10641955.2016.1181180.Search in Google Scholar PubMed

10. Saito, S, Nakashima, A. A review of the mechanism for poor placentation in early-onset preeclampsia: the role of autophagy in trophoblast invasion and vascular remodeling. J Reprod Immunol 2014;101–102:80–8. https://doi.org/10.1016/j.jri.2013.06.002.Search in Google Scholar PubMed

11. Goulopoulou, S, Davidge, ST. Molecular mechanisms of maternal vascular dysfunction in preeclampsia. Trends Mol Med 2015;21:88–97. https://doi.org/10.1016/j.molmed.2014.11.009.Search in Google Scholar PubMed

12. Phipps, EA, Thadhani, R, Benzing, T, Karumanchi, SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol 2019;15:275–89. https://doi.org/10.1038/s41581-019-0119-6.Search in Google Scholar PubMed PubMed Central

13. Wang, X, Zhang, Z, Zeng, X, Wang, J, Zhang, L, Song, W, et al.. Wnt/beta-catenin signaling pathway in severe preeclampsia. J Mol Histol 2018;49:317–27. https://doi.org/10.1007/s10735-018-9770-7.Search in Google Scholar PubMed

14. Haram, K, Mortensen, JH, Myking, O, Roald, B, Magann, EF, Morrison, JC. Early development of the human placenta and pregnancy complications. J Matern Fetal Neonatal Med 2020;33:3538–45. https://doi.org/10.1080/14767058.2019.1578745.Search in Google Scholar PubMed

15. Sonderegger, S, Husslein, H, Leisser, C, Knofler, M. Complex expression pattern of Wnt ligands and frizzled receptors in human placenta and its trophoblast subtypes. Placenta 2007;28(A Suppl):S97–102. https://doi.org/10.1016/j.placenta.2006.11.003.Search in Google Scholar PubMed PubMed Central

16. Nusse, R, Clevers, H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017;169:985–99. https://doi.org/10.1016/j.cell.2017.05.016.Search in Google Scholar PubMed

17. Lan, L, Wang, W, Huang, Y, Bu, X, Zhao, C. Roles of Wnt7a in embryo development, tissue homeostasis, and human diseases. J Cell Biochem 2019;120:18588–98. https://doi.org/10.1002/jcb.29217.Search in Google Scholar PubMed

18. Noda, M, Vallon, M, Kuo, CJ. The Wnt7’s tale: a story of an orphan who finds her tie to a famous family. Cancer Sci 2016;107:576–82. https://doi.org/10.1111/cas.12924.Search in Google Scholar PubMed PubMed Central

19. Ma, AY, Xie, SW, Zhou, JY, Zhu, Y. Nomegestrol acetate suppresses human endometrial cancer RL95-2 cells proliferation in vitro and in vivo possibly related to upregulating expression of SUFU and Wnt7a. Int J Mol Sci 2017;18:1337. https://doi.org/10.3390/ijms18071337.Search in Google Scholar PubMed PubMed Central

20. Zhou, Y, Nathans, J. Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Dev Cell 2014;31:248–56. https://doi.org/10.1016/j.devcel.2014.08.018.Search in Google Scholar PubMed PubMed Central

21. Keller, A. Breaking and building the wall: the biology of the blood-brain barrier in health and disease. Swiss Med Wkly 2013;143:w13892. https://doi.org/10.4414/smw.2013.13892.Search in Google Scholar PubMed

22. Cullen, M, Elzarrad, MK, Seaman, S, Zudaire, E, Stevens, J, Yang, MY, et al.. GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc Natl Acad Sci USA 2011;108:5759–64. https://doi.org/10.1073/pnas.1017192108.Search in Google Scholar PubMed PubMed Central

23. Liang, M, Niu, J, Zhang, L, Deng, H, Ma, J, Zhou, W, et al.. Gene expression profiling reveals different molecular patterns in G-protein coupled receptor signaling pathways between early- and late-onset preeclampsia. Placenta 2016;40:52–9. https://doi.org/10.1016/j.placenta.2016.02.015.Search in Google Scholar PubMed

24. Rana, S, Lemoine, E, Granger, JP, Karumanchi, SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res 2019;124:1094–112. https://doi.org/10.1161/circresaha.118.313276.Search in Google Scholar PubMed

25. Chen, DB, Magness, RR. Vascular smooth muscle cells during spiral artery remodeling in early human pregnancy dagger. Biol Reprod 2021;104:252–4. https://doi.org/10.1093/biolre/ioaa220.Search in Google Scholar PubMed PubMed Central

26. Maducolil, MK, Al-Obaidly, S, Olukade, T, Salama, H, AlQubaisi, M, Al Rifai, H. Pre-eclampsia: incidence, determinants, and pregnancy outcomes from maternity hospitals in Qatar: a population-based case-control study. J Matern Fetal Neonatal Med 2021;35:1–9. https://doi.org/10.1080/14767058.2021.1937983.Search in Google Scholar PubMed

27. Masturzo, B, Franze, V, Germano, C, Attini, R, Gennarelli, G, Lezo, A, et al.. Risk of adverse pregnancy outcomes by pre-pregnancy Body Mass Index among Italian population: a retrospective population-based cohort study on 27,807 deliveries. Arch Gynecol Obstet 2019;299:983–91. https://doi.org/10.1007/s00404-019-05093-0.Search in Google Scholar PubMed

28. Goolam, M, Scialdone, A, Graham, SJL, Macaulay, IC, Jedrusik, A, Hupalowska, A, et al.. Heterogeneity in Oct4 and Sox2 targets biases cell fate in 4-cell mouse embryos. Cell 2016;165:61–74. https://doi.org/10.1016/j.cell.2016.01.047.Search in Google Scholar PubMed PubMed Central

29. Yang, HY. MiR-133b regulates oxidative stress injury of trophoblasts in preeclampsia by mediating the JAK2/STAT3 signaling pathway. J Mol Histol 2021;52:1177–88. https://doi.org/10.1007/s10735-021-10024-y.Search in Google Scholar PubMed

30. Zhou, W, Xue, P, Yang, Y, Xia, L, Yu, B. Research progress on N6-methyladenosine in the human placenta. J Perinat Med 2022;50:1115–23. https://doi.org/10.1515/jpm-2021-0665.Search in Google Scholar PubMed

31. Wang, L, Yuan, X, Zhou, X. Expression pattern and clinical significance of microRNA-let-7a and IFN-gamma in placental tissue of patients with preeclampsia with severe features. J Perinat Med 2022;50:1142–9. https://doi.org/10.1515/jpm-2021-0133.Search in Google Scholar PubMed

32. Gunel, T, Hosseini, MK, Gumusoglu, E, Kisakesen, HI, Benian, A, Aydinli, K. Expression profiling of maternal plasma and placenta microRNAs in preeclamptic pregnancies by microarray technology. Placenta 2017;52:77–85. https://doi.org/10.1016/j.placenta.2017.02.019.Search in Google Scholar PubMed

33. 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;20:981–9. https://doi.org/10.1177/1933719112472740.Search in Google Scholar PubMed PubMed Central

34. Zhang, Z, Li, H, Zhang, L, Jia, L, Wang, P. Differential expression of beta-catenin and Dickkopf-1 in the third trimester placentas from normal and preeclamptic pregnancies: a comparative study. Reprod Biol Endocrinol 2013;11:17. https://doi.org/10.1186/1477-7827-11-17.Search in Google Scholar PubMed PubMed Central

35. Chaiworapongsa, T, Romero, R, Whitten, A, Tarca, AL, Bhatti, G, Draghici, S, et al.. Differences and similarities in the transcriptional profile of peripheral whole blood in early and late-onset preeclampsia: insights into the molecular basis of the phenotype of preeclampsiaa. J Perinat Med 2013;41:485–504. https://doi.org/10.1515/jpm-2013-0082.Search in Google Scholar PubMed PubMed Central

36. L’Omelette, AD, Dawonauth, L, Rademacher, L, Robillard, PY, Scioscia, M, Jankee, S, et al.. New insights into early and late onset subgroups of preeclampsia from longitudinal vs. cross-sectional analysis of urinary inositol-phosphoglycan P-type. J Reprod Immunol 2018;125:64–71. https://doi.org/10.1016/j.jri.2017.11.006.Search in Google Scholar PubMed

37. Cho, C, Smallwood, PM, Nathans, J. Reck and Gpr124 are essential receptor cofactors for Wnt7a/Wnt7b-specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation. Neuron 2017;95:1221–5. https://doi.org/10.1016/j.neuron.2017.07.031.Search in Google Scholar PubMed PubMed Central

38. King, ML, Lindberg, ME, Stodden, GR, Okuda, H, Ebers, SD, Johnson, A, et al.. WNT7A/beta-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene 2015;34:3452–62. https://doi.org/10.1038/onc.2014.277.Search in Google Scholar PubMed PubMed Central

39. Merritt, MA, Parsons, PG, Newton, TR, Martyn, AC, Webb, PM, Green, AC, et al.. Expression profiling identifies genes involved in neoplastic transformation of serous ovarian cancer. BMC Cancer 2009;9:378. https://doi.org/10.1186/1471-2407-9-378.Search in Google Scholar PubMed PubMed Central

Received: 2022-11-22

Accepted: 2023-08-17

Published Online: 2023-09-12

Published in Print: 2024-01-29

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpm-2022-0565

Keywords for this article

early-onset preeclampsia; Wnt7a; GPR124; placenta; trophoblast