2024 / 01

DOI: 10.24075/brsmu.2024.010

ORIGINAL RESEARCH

Emerging prediction of preeclampsia based on the expression of exosomal SUMO proteins

Gusar VA, Timofeeva AV, Fedorov IS, Tarasova AM, Suhova YuV, Ivanets TYu
About authors

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia

Correspondence should be addressed: Vladoslava A. Gusar
Akademika Oparina, 4, Moscow, 117997, Russia; ur.liam@rasug_v

About paper

Funding: the study was supported by the RSF grant [22-15-00363 “Epigenetic and biochemical aspects of abnormal pregnancy in disturbances of the trophoblast invasive properties: from early diagnosis to prevention of maternal and perinatal morbidity”].

Author contribution: Gusar VA, Timofeeva AV — study concept; Fedorov IS — statistical analysis, graphic design; Gusar VA, Tarasova AM — research procedure (western blotting); Sukhova YuV, Ivanets TYu — providing the clinical basis, assessment of hormones; Gusar VA — data analysis/interpretation, manuscript writing; Timofeeva AV — editing.

Compliance with ethical standards: the study was approved by the Ethics Committee of the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology (protocol № 13 dated 12 October 2015); the informed consent was obtained from all the patients enrolled.

Received: 2024-01-29 Accepted: 2024-02-20 Published online: 2024-02-29
|
  1. Ilekis JV, Tsilou E, Fisher S, et al. Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. American Journal of Obstetrics and Gynecology. 2016; 215 (1): S1–S46.
  2. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, сhallenges, and perspectives. 2019; Circ Res. 124 (7): 1094–1112.
  3. Staff AC. The two-stage placental model of preeclampsia: An update. Journal of Reproductive Immunology. 2019; 134–135: 1–10.
  4. Tenório MB, Ferreira RC, Moura FA, Bueno NB, de Oliveira ACM, Goulart MOF. Cross-Talk between Oxidative Stress and Inflammation in Preeclampsia. Oxidative Medicine and Cellular Longevity. 2019; 2019: 1–26.
  5. Melchiorre K, Giorgione V, Thilaganathan B. The placenta and preeclampsia: villain or victim? American Journal of Obstetrics and Gynecology. 2022; 226 (2): S954–S962.
  6. Chen CW, Jaffe IZ, Karumanchi SA. Pre-eclampsia and cardiovascular disease. Cardiovascular Research. 2014; 101 (4): 579–86.
  7. Ritz E, Amann K, Koleganova N, Benz K. Prenatal programming— effects on blood pressure and renal function. Nat Rev Nephrol. 2011; 7 (3): 137–44.
  8. Poon LC, Shennan A, Hyett JA, et al. The International Federation of Gynecology and Obstetrics ( FIGO ) initiative on preeclampsia: a pragmatic guide for first‐trimester screening and prevention. Int J Gynecol Obstet. 2019; 145 (S1): 1–33.
  9. ACOG. Obstetrics & Gynecology. 2019; 133 (1): 1–1.
  10. Yagel S, Cohen SM, Goldman-Wohl D. An integrated model of preeclampsia: a multifaceted syndrome of the maternal cardiovascular-placental-fetal array. American Journal of Obstetrics and Gynecology. 2022; 226 (2): S963–S972.
  11. Gobble RM, Groesch KA, Chang M, Torry RJ, Torry DS. Differential regulation of human PlGF gene expression in trophoblast and nontrophoblast cells by oxygen tension. Placenta. 2009; 30 (10): 869–75.
  12. Chang M, Mukherjea D, Gobble RM, Groesch KA, Torry RJ, Torry DS. Glial cell missing regulates Placental Growth Factor (PGF) gene transcription in human trophoblast. Biology of Reproduction. 2008; 78 (5): 841–51.
  13. Baczyk D, Kibschull M, Mellstrom B, et al. DREAM mediated regulation of GCM1 in the human placental trophoblast. PLoS ONE. 2013; 8 (1): e51837.
  14. Chou C-C, Chang C, Liu J-H, Chen L-F, Hsiao C-D, Chen H. Small ubiquitin-like modifier modification regulates the DNA binding activity of glial cell missing Drosophila Homolog a. Journal of Biological Chemistry. 2007; 282 (37): 27239–49.
  15. Enserink JM. Sumo and the cellular stress response. Cell Div. 2015; 10 (1): 4.
  16. He J, Cheng J, Wang T. SUMOylation-Mediated Response to Mitochondrial Stress. IJMS. 2020; 21 (16): 5657.
  17. Kunz K, Wagner K, Mendler L, Hölper S, Dehne N, Müller S. SUMO signaling by hypoxic inactivation of SUMO-specific isopeptidases. Cell Reports. 2016; 16 (11): 3075–86.
  18. Karhausen J, Ulloa L, Yang W. SUMOylation connects cell stress responses and inflammatory control: lessons from the gut as a model organ. Front Immunol. 2021; 12: 646633.
  19. Chang H-M, Yeh ETH. SUMO: from bench to bedside. Physiological Reviews. 2020; 100 (4): 1599–619.
  20. Baczyk D, Drewlo S, Kingdom JCP. Emerging role of SUMOylation in placental pathology. Placenta. 2013; 34 (7): 606–12.
  21. Kondoh K, Akahori H, Muto Y, Terada T. Identification of key genes and pathways associated with preeclampsia by a WGCNA and an evolutionary approach. Genes. 2022; 13 (11): 2134.
  22. Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. 2021; 19 (1): 47.
  23. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014; 14 (3): 195–208.
  24. Salomon C, Kobayashi M, Ashman K, Sobrevia L, Mitchell MD, Rice GE. Hypoxia-induced changes in the bioactivity of cytotrophoblast-derived exosomes. PLoS ONE. 2013; 8 (11): e79636.
  25. Tannetta DS, Dragovic RA, Gardiner C, Redman CW, Sargent IL. Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and Endoglin. PLoS ONE. 2013; 8 (2): e56754.
  26. Salomon C, Guanzon D, Scholz-Romero K, et al. Placental exosomes as early biomarker of preeclampsia: potential role of exosomal microRNAs across gestation. The Journal of Clinical Endocrinology & Metabolism. 2017; 102 (9): 3182–94.
  27. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013; 4 (1): 2980.
  28. Gusar VA, Timofeeva AV, Chagovets VV, Kan NE, Ivanets TYu, Sukhikh GT. Regulation of the placental growth factor mediated by sumoylation and expression of miR-652-3p in pregnant women with early-onset preeclampsia. Bull Exp Biol Med. 2022; 174 (1): 174–8.
  29. Gusar V, Timofeeva A, Chagovets V, et al. Diagnostic potential of exosomal hypoxamiRs in the context of hypoxia–sumoylation– hypoxamiRs in early onset preeclampsia at the preclinical stage. Life. 2022; 12 (1): 101.
  30. Chiarello DI, Salsoso R, Toledo F, Mate A, Vázquez CM, Sobrevia L. Foetoplacental communication via extracellular vesicles in normal pregnancy and preeclampsia. Molecular Aspects of Medicine. 2018; 60: 69–80.
  31. Salomon C, Torres MJ, Kobayashi M, et al. A Gestational Ppofile of placental exosomes in maternal plasma and their effects on endothelial cell migration. PLoS ONE. 2014; 9 (6): e98667.
  32. Tannetta D, Collett G, Vatish M, Redman C, Sargent I. Syncytiotrophoblast extracellular vesicles — Circulating biopsies reflecting placental health. Placenta. 2017; 52: 134–8.
  33. Hendriks IA, D’Souza RCJ, Yang B, Verlaan-de Vries M, Mann M, Vertegaal ACO. Uncovering global SUMOylation signaling networks in a site-specific manner. Nat Struct Mol Biol. 2014; 21 (10): 927–36.
  34. Hay RT. SUMO. Molecular Cell. 2005; 18 (1): 1–12.
  35. Baczyk D, Audette MC, Drewlo S, Levytska K, Kingdom JC. SUMO-4: a novel functional candidate in the human placental protein SUMOylation machinery. PLoS ONE. 2017; 12 (5): e0178056.
  36. Anderson DB, Wilkinson KA, Henley JM. Protein SUMOylation in neuropathological conditions. Drug News & Perspectives. 2009; 22 (5): 255.
  37. Bawa-Khalfe T, Yeh ETH. SUMO losing balance: SUMO proteases disrupt SUMO homeostasis to facilitate cancer development and Progression. Genes & Cancer. 2010; 1 (7): 748–52.
  38. Baczyk D, Audette MC, Coyaud E, Raught B, Kingdom JC. Spatiotemporal distribution of small ubiquitin-like modifiers during human placental development and in response to oxidative and inflammatory stress: Placental distribution of small ubiquitin-like modifiers. J Physiol. 2018; 596 (9): 1587–600.
  39. Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitinrelated protein modifiers SUMO-1 versus SUMO-2/3. Journal of Biological Chemistry. 2000; 275 (9): 6252–8.
  40. Hasegawa Y, Yoshida D, Nakamura Y, Sakakibara S. Spatiotemporal distribution of SUMOylation components during mouse brain development: Sumo-ylation during brain development. J Comp Neurol. 2014; 522 (13): 3020–36.
  41. Chalkiadaki A, Talianidis I. SUMO-dependent compartmentalization in promyelocytic leukemia protein nuclear bodies prevents the access of LRH-1 to chromatin. Molecular and Cellular Biology. 2005; 25 (12): 5095–105.
  42. Snider NT, Omary MB. Post-translational modifications of intermediate filament proteins: mechanisms and functions. Nat Rev Mol Cell Biol. 2014; 15 (3): 163–77.
  43. Vassileva MT, Matunis MJ. SUMO modification of heterogeneous nuclear ribonucleoproteins. Molecular and Cellular Biology. 2004; 24 (9): 3623–32.
  44. Vertegaal ACO, Ogg SC, Jaffray E, et al. A Proteomic study of SUMO-2 target proteins. Journal of Biological Chemistry. 2004; 279 (32): 33791–8.
  45. Bhattacharjee J, Alahari S, Sallais J, Tagliaferro A, Post M, Caniggia I. Dynamic regulation of HIF1Α stability by SUMO2/3 and SENP3 in the human placenta. Placenta. 2016; 40: 8–17.
  46. Xu Y, Zuo Y, Zhang H, et al. Induction of SENP1 in endothelial cells contributes to hypoxia-driven VEGF expression and angiogenesis. Journal of Biological Chemistry. 2010; 285 (47): 36682–8.
  47. Zhou HJ, Xu Z, Wang Z, et al. SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis. Nat Commun. 2018; 9 (1): 3303.
  48. McCaig D, Lyall F. Hypoxia upregulates GCM1 in human placenta explants. hypertension in pregnancy. 2009; 28 (4): 457–72.
  49. Kohli S, Hoffmann J, Lochmann F, et al. p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction. Cell Death Dis. 2017; 8 (4): e2730–e2730.
  50. Chang C-W, Chang G-D, Chen H. A novel cyclic AMP/Epac1/ CaMKI signaling cascade promotes GCM1 desumoylation and placental cell fusion. Molecular and Cellular Biology. 2011; 31 (18): 3820–31.
  51. Luo J, Ashikaga E, Rubin PP, et al. Receptor trafficking and the regulation of synaptic plasticity by SUMO. Neuromol Med. 2013; 15 (4): 692–706.
  52. Maynard SE, Min J-Y, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111 (5): 649–58.
  53. Redman CWG, Staff AC. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. American Journal of Obstetrics and Gynecology. 2015; 213 (4): S9.e1-S9.e4.
  54. Dymara-Konopka W, Laskowska M, Grywalska E, Hymos A, Błażewicz A, Leszczyńska-Gorzelak B. Similar pro- and antiangiogenic profiles close to delivery in different clinical presentations of two pregnancy syndromes: preeclampsia and fetal growth restriction. IJMS. 2023; 24 (2): 972.
  55. Keikkala E, Vuorela P, Laivuori H, Romppanen J, Heinonen S, Stenman U-H. First trimester hyperglycosylated human chorionic gonadotrophin in serum — a marker of early-onset preeclampsia. Placenta. 2013; 34 (11): 1059–65.
  56. Morris RK, Bilagi A, Devani P, Kilby MD. Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and metaanalysis: Systematic review association serum PAPP-A and adverse pregnancy outcome. Prenat Diagn. 2017; 37 (3): 253–65.
  57. Krantz D, Goetzl L, Simpson JL, et al. Association of extreme first-trimester free human chorionic gonadotropin-β, pregnancyassociated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. American Journal of Obstetrics and Gynecology. 2004; 191 (4): 1452–8.