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Abnormal cGMP-dependent protein kinase I-mediated decidualization in preeclampsia

Abstract

Defective decidual function contributes to the pathogenesis of preeclampsia. However, the precise mechanism of defective decidua during preeclampsia has not been characterized. During decidualization, endometrial stromal cells undergo phenotypic changes that are consistent with mesenchymal-epithelial transition (MET). cGMP-dependent kinase protein I (PKGI)/VASP signaling is important in cell motility proliferation, differentiation and cell adhesion. To investigate this aim, we analyzed PKGI levels, phosphorylated VASP protein levels, and eNOS and sGC protein expression levels during pregnancy complicated by preeclampsia, which indicated that PKGI/VASP signaling function is decreased by the condition. Moreover, we evaluated the differential expression of genes that regulate MET in the decidua resulting from preeclampsia and healthy pregnancies. We discovered that vimentin mRNA levels are decreased in the decidua of preeclampsia, which indicates that excessive MET occurs in the decidua of preeclampsia pregnancies. A fundamental developmental MET program occurred in response to signaling pathways. These results suggest the important role of decreased PKGI/VASP signaling during excessive MET in the pathogenesis of preeclampsia.

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References

  1. Knight M, Tuffnell D. A view from the UK: the UK and Ireland confidential enquiry into maternal deaths and morbidity. Clin Obstet Gynecol. 2018;61:347–58.

    Article  Google Scholar 

  2. Juan L, Xiaohong L, Chuyun K, Yanping W, Rachel KX, CM M, et al. Maternal mortality ratios in 2852 Chinese counties, 1996–2015, and achievement of Millennium Development Goal 5 in China: a subnational analysis of the Global Burden of Disease Study 2016. Lancet. 2019;393:241–52.

    Article  Google Scholar 

  3. Haram K, Mortensen JH, Myking O, Roald B, Magann EF, Morrison JC. Early development of the human placenta and pregnancy complications. J Maternal Fetal Neonatal Med. 2020;33:3538–45.

    Article  Google Scholar 

  4. Garrido-Gomez T, Dominguez F, Quinonero A, Diaz-Gimeno P, Kapidzic M, Gormley M, et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc Natl Acad Sci USA. 2017;114:E8468–77.

    Article  CAS  Google Scholar 

  5. Tong J, Zhao W, Lv H, Li W-P, Chen Z, Zhang C. Transcriptomic profiling in human decidua of severe preeclampsia detected by RNA sequencing. J Cell Biochem. 2017;119:607–15.

    Article  Google Scholar 

  6. Mori M, Bogdan A, Balassa T, Csabai T, Szekeres-Bartho J. The decidua-the maternal bed embracing the embryo-maintains the pregnancy. Semin Immunopathol. 2016;38:635–49.

    Article  Google Scholar 

  7. Patterson AL, Zhang L, Arango NA, Teixeira J, Pru JK. Mesenchymal-to-epithelial transition contributes to endometrial regeneration following natural and artificial decidualization. Stem Cells Dev. 2013;22:964–74.

    Article  CAS  Google Scholar 

  8. Rutherford RA, McCarthy A, Sullivan MH, Elder MG, Polak JM, Wharton J. Nitric oxide synthase in human placenta and umbilical cord from normal, intrauterine growth-retarded and pre-eclamptic pregnancies. Br J Pharmacol. 1995;116:3099–109.

    Article  CAS  Google Scholar 

  9. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol. 1997;272:R441–63.

    CAS  PubMed  Google Scholar 

  10. Bolnick JM, Kilburn BA, Bolnick AD, Diamond MP, Singh M, Hertz M, et al. Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3’,5’-cyclic monophosphate signaling. Fertil Steril. 2015;103:1587–95. e1581–82.

    Article  CAS  Google Scholar 

  11. Dordea AC, Sweeney M, Taggart J, Lartey J, Wessel H, Robson SC, et al. Differential vasodilation of human placental and myometrial arteries related to myofilament Ca(2+)-desensitization and the expression of Hsp20 but not MYPT1. Mol Hum Reprod. 2013;19:727–36.

    Article  CAS  Google Scholar 

  12. Lund N, Henrion D, Tiede P, Ziche M, Schunkert H, Ito WD. Vimentin expression influences flow dependent VASP phosphorylation and regulates cell migration and proliferation. Biochemical biophysical Res Commun. 2010;395:401–6.

    Article  CAS  Google Scholar 

  13. Kayisli UA, Demir R, Erguler G, Arici A. Vasodilator-stimulated phosphoprotein expression and its cytokine-mediated regulation in vasculogenesis during human placental development. Mol Hum Reprod. 2002;8:1023–30.

    Article  CAS  Google Scholar 

  14. Chu S, Zhang X, Sun Y, Liang Y, Sun J, Lu M, et al. Atrial natriuretic peptide inhibits epithelial-mesenchymal transition (EMT) of bronchial epithelial cells through cGMP/PKG signaling by targeting Smad3 in a murine model of allergic asthma. Exp lung Res. 2019;45:245–54.

    Article  CAS  Google Scholar 

  15. Vyas-Read S, Shaul PW, Yuhanna IS, Willis BC. Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2007;293:L212–21.

    Article  CAS  Google Scholar 

  16. Duran-Reyes G, Gomez-Melendez MR, Morali-de la Brena G, Mercado-Pichardo E, Medina-Navarro R, Hicks-Gomez JJ. Nitric oxide synthesis inhibition suppresses implantation and decreases cGMP concentration and protein peroxidation. Life Sci. 1999;65:2259–68.

    Article  CAS  Google Scholar 

  17. ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1–25.

  18. Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, et al. Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PloS ONE. 2010;5:e10258.

    Article  Google Scholar 

  19. Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366:l2381.

    Google Scholar 

  20. McCauley SD, Gilchrist M, Befus AD. Nitric oxide: a major determinant of mast cell phenotype and function. Mem Inst Oswaldo Cruz. 2005;100:11–14.

    Article  CAS  Google Scholar 

  21. Cokic VP, Schechter AN. Effects of nitric oxide on red blood cell development and phenotype. Curr Top Dev Biol. 2008;82:169–215.

    Article  CAS  Google Scholar 

  22. Wolfertstetter S, Huettner JP, Schlossmann J. cGMP-dependent protein kinase inhibitors in health and disease. Pharmaceuticals. 2013;6:269–86.

    Article  CAS  Google Scholar 

  23. Brennecke SP, Gude NM, Di Iulio JL, King RG. Reduction of placental nitric oxide synthase activity in pre-eclampsia. Clin Sci. 1997;93:51–55.

    Article  CAS  Google Scholar 

  24. Kayisli UA, Selam B, Demir R, Arici A. Expression of vasodilator-stimulated phosphoprotein in human placenta: possible implications in trophoblast invasion. Mol Hum Reprod. 2002;8:88–94.

    Article  CAS  Google Scholar 

  25. Ali M, Rogers LK, Heyob KM, Buhimschi CS, Buhimschi IA. Changes in vasodilator-stimulated phosphoprotein phosphorylation, Profilin-1, and Cofilin-1 in accreta and protection by DHA. Reprod Sci. 2019;26:757–65.

    Article  CAS  Google Scholar 

  26. TML TAWyatt, Pryzwansky KB. Vimentin is transiently co-localized with and phosphorylated by cyclic GMP-dependent protein kinase in formylpeptide-stimulated neutrophils. J Biol Chem. 1991;266:21274–80.

    Article  Google Scholar 

  27. Owusu-Akyaw A, Krishnamoorthy K, Goldsmith LT, Morelli SS. The role of mesenchymal-epithelial transition in endometrial function. Hum Reprod Update. 2019;25:114–33.

    Article  CAS  Google Scholar 

  28. Zhang XH, Liang X, Liang XH, Wang TS, Qi QR, Deng WB, et al. The mesenchymal-epithelial transition during in vitro decidualization. Reprod Sci. 2013;20:354–60.

    Article  Google Scholar 

  29. Patterson AL, Pirochta J, Tufano SY, Teixeira JM. Gain-of-function beta-catenin in the uterine mesenchyme leads to impaired implantation and decidualization. J Endocrinol. 2017;233:119–30.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Key R&D Program of China (No. 2017YFC1001402 and 2018YFC10029002), the National Natural Science Foundation (No. 81830045, 81671533 and 82071652), and the General Program of Guangdong Province Natural Science Foundation (No. 2020A1515010273).

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Correspondence to Dunjin Chen or Lili Du.

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Chen, J., Ren, W., Lin, L. et al. Abnormal cGMP-dependent protein kinase I-mediated decidualization in preeclampsia. Hypertens Res 44, 318–324 (2021). https://doi.org/10.1038/s41440-020-00561-6

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