Transcriptional profile features in patients with early and late preeclampsia

   Aim: to assess the molecular mechanisms in developing various clinical phenotypes of preeclampsia (PE) by analyzing specific placental tissue transcriptome patterns.

   Materials and Methods. The prospective observational comparative study in parallel groups enrolled 43 pregnant women divided into 2 groups: main group – 23 pregnant women with diagnosed PE and control group – 20 apparently healthy women with uncomplicated pregnancy course, delivery and the postpartum period. To examine PE phenotypic features, the main group of pregnant women with PE was subsequently divided into 2 subgroups according to the date of pathology onset: early (n = 10) and late (n = 13) PE. Using the whole-genome next-generation sequencing (NGS), a comparative analysis of altered 18 microRNA level in placental tissue was carried out.

   Results. Pregnant women with early PE compared to the control group were characterized by significantly low expression level for hsa-miR-656-3p (p < 0.001), hsa-miR-323a-5p (p = 0.017), hsa-miR-519c-3p (p = 0.019), hsa-let-7i-5p (p = 0.019), hsa-miR-433-3p (p = 0.019), hsa-let-7g-5p (p = 0.030), hsa-miR-214-5p (p = 0.030), hsa-miR-27a-5p (p = 0.031), hsa-miR-339-5p (p = 0.041), hsa-miR-524-5p (p = 0.045), hsa-miR-1283 (p = 0.049) and high expression for hsa-miR-151a-5p (p = 0.007), hsa-miR-4521 (p = 0.018), hsa-miR-30d-5p (p = 0.026), hsa-miR-548l (p = 0.027), hsa-miR-133b (p = 0.034), hsa-miR-424-5p (p = 0.042), hsa-miR-211-5p (p = 0.049). Patients with late PE had significantly decreased expression for hsa-miR-656-3p (p = 0.050) and
hsa-miR-574-3p (p = 0.017) as well as a significantly higher for hsa-miR-211-5p (p = 0.001) compared to the control group. Subgroup of women with early vs. late onset PE was characterized by significantly decreased expression level for hsa-miR-323-5p (p = 0.007) and overexpressed hsa-miR-30d-5p (p = 0.002), hsa-miR-5481 (p = 0.027).

   Conclusion. The noted multidirectional expression for some microRNAs in subgroups of PE patients confirms the validity for stratification of such pathology based on two distinct phenotypic manifestations (early and late forms) and indicates the existence of different pathophysiological vectors in PE formation.

1. Filippov O.S., Guseva E.V. Maternal mortality in the Russian Federation in 2019. [Materinskaya smertnost' v Rossijskoj Federacii v 2019 g]. Problemy reprodukcii. 2020;26(6–2):8–26. (In Russ.). doi: 10.17116/repro2020260628.

2. Sidorova I.S., Nikitina N.A., Filippov O.S. et al. Current issues in preeclampsia: a ten-year analysis of maternal mortality. [Reshennye i nereshennye voprosy preeklampsii po rezul'tatam analiza materinskoj smertnosti za poslednie 10 let]. Akusherstvo i ginekologiya. 2021;(4):64–74. (In Russ.). doi: 10.18565/aig.2021.4.64-74.

3. Aldridge S., Teichmann S.A. Single cell transcriptomics comes of age. Nat Commun. 2020;11(1):4307. doi: 10.1038/s41467-020-18158-5.

4. Gong S., Gaccioli F., Dopierala J. et al. The RNA landscape of the human placenta in health and disease. Nat Commun. 2021;12(1):2639. doi: 10.1038/s41467-021-22695-y.

5. Clinical guidelines – Preeclampsia. Eclampsia. Edema, proteinuria and hypertensive disorders during pregnancy, childbirth and the postpartum period – 2021-2022-2023 (24. 06. 2021). [Klinicheskie rekomendacii –Preeklampsiya. Eklampsiya. Oteki, proteinuriya i gipertenzivnye rasstrojstva vo vremya beremennosti, v rodah i poslerodovom periode – 2021-2022-2023 (24. 06. 2021)]. Moscow: Ministerstvo zdravoohraneniya Rossijskoj Federacii, 2021. 54 p. (In Russ.). Available at: http://disuria.ru/_ld/10/1046_kr21O10O16MZ.pdf. [Accessed: 25. 12. 2023].

6. Howe C.G., Foley H.B., Kennedy E.M. et al. Extracellular vesicle microRNA in early versus late pregnancy with birth outcomes in the MADRES study. Epigenetics. 2022;17(3):269–85. doi: 10.1080/15592294.2021.1899887.

7. Kuokkanen S., Chen B., Ojalvo L. et al. Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium. Biol Reprod. 2010;82(4):791–801. doi: 10.1095/biolreprod.109.081059.

8. Cai J.L., Liu L.L., Hu Y. et al. Polychlorinated biphenyls impair endometrial receptivity in vitro via regulating mir-30d expression and epithelial mesenchymal transition. Toxicology. 2016;365:25–34. doi: 10.1016/j.tox.2016.07.017.

9. Zhao Y., He D., Zeng H. et al. Expression and significance of miR-30d-5p and SOCS1 in patients with recurrent implantation failure during implantation window. Reprod Biol Endocrinol. 2021;19(1):138. doi: 10.1186/s12958-021-00820-2.

10. Balaguer N., Moreno I., Herrero M. et al. MicroRNA-30d deficiency during preconception affects endometrial receptivity by decreasing implantation rates and impairing fetal growth. Am J Obstet Gynecol. 2019;221(1):46. e1–46.e16. doi: 10.1016/j.ajog.2019.02.047.

11. Zhang L., Li K., Tian S. et al. Down-regulation of microRNA-30d-5p is associated with gestational diabetes mellitus by targeting RAB8A. J Diabetes Complications. 2021;35(8):107959. doi: 10.1016/j.jdiacomp.2021.107959.

12. Sun Y., Bilan P.J., Liu Z., Klip A. Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells. Proc Natl Acad Sci U S A. 2010;107(46):19909–14. doi: 10.1073/pnas.1009523107.

13. Ishikura S., Bilan P.J., Klip A. Rabs 8A and 14 are targets of the insulin-regulated Rab-GAP AS160 regulating GLUT4 traffic in muscle cells. Biochem Biophys Res Commun. 2007;353(4):1074–9. doi: 10.1016/j.bbrc.2006.12.140.

14. Wall A.A., Luo L., Hung Y. et al. Small GTPase Rab8a-recruited phosphatidylinositol 3-kinase γ regulates signaling and cytokine outputs from endosomal toll-like receptors. J Biol Chem. 2017;292(11):4411–22. doi: 10.1074/jbc.M116.766337.

15. Nakajo A., Yoshimura S., Togawa H. et al. EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells. J Cell Biol. 2016;212(3):297–306. doi: 10.1083/jcb.201508086.

16. Wright K.R., Mitchell B., Santanam N. Redox regulation of microRNAs in endometriosis-associated pain. Redox Biol. 2017;12:956–66. doi: 10.1016/j.redox.2017.04.037.

17. Cai H., Zhou H., Miao Y. et al. MiRNA expression profiles reveal the involvement of miR-26a, miR-548l and miR-34a in hepatocellular carcinoma progression through regulation of ST3GAL5. Lab Invest. 2017;97(5):530–42. doi: 10.1038/labinvest.2017.12.

18. Liu C., Yang H., Xu Z. et al. microRNA-548l is involved in the migration and invasion of non-small cell lung cancer by targeting the AKT1 signaling pathway. J Cancer Res Clin Oncol. 2015;141(3):431–41. doi: 10.1007/s00432-014-1836-7.

19. Cheng B., Li J.Y., Li X.C. et al. MiR-323b-5p acts as a novel diagnostic biomarker for critical limb ischemia in type 2 diabetic patients. Sci Rep. 2018;8(1):15080. doi: 10.1038/s41598-018-33310-4.

20. Hedley P.L., Larsen S.O., Wøjdemann K.R. et al. First trimester maternal serum microRNA expression profile differentiates between uncomplicated pregnancies, and pregnancies which develop pre-eclampsia. medRxiv. 2023;23289708. doi: 10.1101/2023.05.09.23289708.