Skip to main content
Log in

The Expression and Contribution of SRCs with Preeclampsia Placenta

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The steroid hormones act by binding to their receptors and subsequently interacting with coactivators. Several classes of coactivators have been identified and shown to be essential in estradiol (E2) responsiveness. The major coregulators are the p160 steroid receptor coactivator (SRC) family. Although the function of SRCs in other organs has been well studied, it has not been thoroughly studied in the placenta. In addition, the correlation between preeclampsia (PE) and SRCs has not been examined previously. Therefore, we compared the expression patterns of SRCs in normal and PE placentas. In human PE placental tissues, SRC-1 mRNA, and protein levels were downregulated in the PE group. In addition, to assess the expression of SRCs in a PE environment, we used Reduced Uterine Perfusion Pressure (RUPP) model and placental cells were cultured in hypoxia condition. SRC-1 proteins were reduced in the placenta of PE-like rat RUPP model. Furthermore, SRCs proteins were significantly downregulated in hypoxia-grown placental cells. To examine the interaction between estrogen receptors (ERs) and SRC-1 protein, we performed co-immunoprecipitation. The interaction of SRC-1 with ERα was significantly stronger than that with ERβ. In PE placenta, the interaction of both ERα and ERβ with SRC-1 was stronger than that in normal placenta. In summary, our results demonstrate that expression levels of SRC-1, not SRC-2 and SRC-3, were decreased in hypoxia-induced PE placenta, which may further reduce the signaling of sex steroid hormones such as E2. The dysregulated signaling of E2 by SRC-1 expression could be associated with the PE placental symptoms of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res. 2004;114(5–6):397–407.

    Article  CAS  PubMed  Google Scholar 

  2. Ueki N, Takeda S, Koya D, Kanasaki K. The relevance of the renin-angiotensin system in the development of drugs to combat preeclampsia. Int J Endocrinol 2015;2015:572713.

  3. Kumar P, Magon N. Hormones in pregnancy. Nigerian medical journal : journal of the Nigeria Medical Association. 2012;53(4):179–83.

    Article  Google Scholar 

  4. McKenna NJ, O'Malley BW. Minireview: nuclear receptor coactivators--an update. Endocrinology. 2002;143(7):2461–5.

    Article  CAS  PubMed  Google Scholar 

  5. Leo C, Chen JD. The SRC family of nuclear receptor coactivators. Gene. 2000;245(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  6. Stashi E, York B, O’Malley BW. Steroid receptor coactivators: servants and masters for control of systems metabolism. Trends in Endocrinology & Metabolism. 2014;25(7):337–47.

    Article  CAS  Google Scholar 

  7. Dasgupta S, Lonard DM, O'Malley BW. Nuclear receptor coactivators: master regulators of human health and disease. Annu Rev Med. 2014;65:279–92.

    Article  CAS  PubMed  Google Scholar 

  8. Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai M-J, O'malley BW. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 1998;279(5358):1922–5.

    Article  CAS  PubMed  Google Scholar 

  9. Han SJ, DeMayo FJ, Xu J, Tsai SY, Tsai M-J, O’malley BW. Steroid receptor coactivator (SRC)-1 and SRC-3 differentially modulate tissue-specific activation functions of the progesterone receptor. Mol Endocrinol. 2006;20(1):45–55.

    Article  CAS  PubMed  Google Scholar 

  10. Xu J, Liao L, Ning G, Yoshida-Komiya H, Deng C, O'Malley BW. The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad Sci. 2000;97(12):6379–84.

    Article  CAS  PubMed  Google Scholar 

  11. Gehin M, Mark M, Dennefeld C, Dierich A, Gronemeyer H, Chambon P. The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP. Mol Cell Biol. 2002;22(16):5923–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Moser M. Working group report on high blood pressure in pregnancy. The Journal of Clinical Hypertension. 2001;3(2):75–88.

    Article  Google Scholar 

  13. Duley L. Pre-eclampsia and the hypertensive disorders of pregnancy. Br Med Bull. 2003;67(1):161–76.

    Article  PubMed  Google Scholar 

  14. Park Y, Cho GJ, Kim LY, Lee TS, Oh MJ, Kim YH. Preeclampsia increases the incidence of postpartum cerebrovascular disease in Korean population. J Korean Med Sci. 2018;33(6):e35.

    Article  PubMed  Google Scholar 

  15. Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig. 2004;11(6):342–52.

    Article  CAS  PubMed  Google Scholar 

  16. Ness RB, Roberts JM. Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications. Am J Obstet Gynecol. 1996;175(5):1365–70.

    Article  CAS  PubMed  Google Scholar 

  17. Fügedi G, Molnár M, Rigó J, Schönléber J, Kovalszky I, Molvarec A. Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study. BMC pregnancy and childbirth. 2014;14(1):395–403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308(5728):1592–4.

    Article  CAS  PubMed  Google Scholar 

  19. Cantonwine DE, McElrath TF, Trabert B, et al. Estrogen metabolism pathways in preeclampsia and normal pregnancy. Steroids. 2019;144:8–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wan J, Hu Z, Zeng K, et al. The reduction in circulating levels of estrogen and progesterone in women with preeclampsia. Pregnancy hypertension. 2018;11:18–25.

    Article  PubMed  Google Scholar 

  21. Shin YY, Jeong JS, Park MN, et al. Regulation of steroid hormones in the placenta and serum of women with preeclampsia. Mol Med Rep. 2018;17(2):2681–8.

    CAS  PubMed  Google Scholar 

  22. Fushima T, Sekimoto A, Minato T, et al. Reduced uterine perfusion pressure (RUPP) model of preeclampsia in mice. PLoS One. 2016;11(5):e0155426.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Li J, LaMarca B, Reckelhoff JF. A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model. Am J Phys Heart Circ Phys. 2012;303(1):H1–8.

    CAS  Google Scholar 

  24. An B-S, Selva DM, Hammond GL, Rivero-Muller A, Rahman N, Leung PC. Steroid receptor coactivator-3 is required for progesterone receptor trans-activation of target genes in response to gonadotropin-releasing hormone treatment of pituitary cells. J Biol Chem. 2006;281(30):20817–24.

    Article  CAS  PubMed  Google Scholar 

  25. Ahmed A. New insights into the etiology of preeclampsia: identification of key elusive factors for the vascular complications. Thromb Res. 2011;127:S72–5.

    Article  CAS  PubMed  Google Scholar 

  26. Ahmad S, Hewett PW, Al-Ani B, et al. Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis. Vascular cell. 2011;3(1):1.

    Article  CAS  Google Scholar 

  27. Redman C, Sargent I. Pre-eclampsia, the placenta and the maternal systemic inflammatory response—a review. Placenta. 2003;24:S21–7.

    Article  PubMed  Google Scholar 

  28. Zeisler H, Jirecek S, Hohlagschwandtner M, Knofler M, Tempfer C, Livingston JC. Concentrations of estrogens in patients with preeclampsia. Wien Klin Wochenschr. 2002;114(12):458–61.

    CAS  PubMed  Google Scholar 

  29. Park MN, Park KH, Lee JE, et al. The expression and activation of sex steroid receptors in the preeclamptic placenta. Int J Mol Med. 2018;41(5):2943–51.

    CAS  PubMed  Google Scholar 

  30. Zhou H-J, Yan J, Luo W, et al. SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res. 2005;65(17):7976–83.

    Article  CAS  PubMed  Google Scholar 

  31. Cai D, Shames DS, Raso MG, et al. Steroid receptor coactivator-3 expression in lung cancer and its role in the regulation of cancer cell survival and proliferation. Cancer Res. 2010;70(16):6477–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Qin L, Liu Z, Chen H, Xu J. The steroid receptor coactivator-1 regulates twist expression and promotes breast cancer metastasis. Cancer Res. 2009;69(9):3819–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim SC, Park M-N, Lee YJ, Joo JK, An B-S. Interaction of steroid receptor coactivators and estrogen receptors in the human placenta. J Mol Endocrinol. 2016;56(3):239–47.

    Article  CAS  PubMed  Google Scholar 

  34. Kanasaki K, Palmsten K, Sugimoto H, et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature. 2008;453(7198):1117.

    Article  CAS  PubMed  Google Scholar 

  35. Tian M, Zhang Y, Liu Z, Sun G, Mor G, Liao A. The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats. Sci Rep. 2016;6:27683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Suzuki H, Ohkuchi A, Shirasuna K, et al. Animal models of preeclampsia: insight into possible biomarker candidates for predicting preeclampsia. Med J Obstet Gynecol. 2014;2(2):1031.

    Google Scholar 

  37. Burleigh D, Kendziorski C, Choi Y, et al. Microarray analysis of BeWo and JEG3 trophoblast cell lines: identification of differentially expressed transcripts. Placenta. 2007;28(5–6):383–9.

    Article  CAS  PubMed  Google Scholar 

  38. Rothbauer M, Patel N, Gondola H, Siwetz M, Huppertz B, Ertl P. A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines. Sci Rep. 2017;7(1):5892.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Schmidt A, Morales-Prieto DM, Pastuschek J, Froehlich K, Markert UR. Only humans have human placentas: molecular differences between mice and humans. J Reprod Immunol. 2015;108:65–71.

    Article  CAS  PubMed  Google Scholar 

  40. Kim J, Lee K-S, Kim J-H, et al. Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway: role of a miR-155/eNOS axis in preeclampsia. Free Radic Biol Med. 2017;104:185–98.

    Article  CAS  PubMed  Google Scholar 

  41. Harmon A, Cornelius D, Amaral L, et al. IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of preeclampsia. Hypertension in pregnancy. 2015;34(3):291–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li P, Gan Y, Xu Y, et al. 17beta-estradiol attenuates TNF-α-induced premature senescence of nucleus pulposus cells through regulating the ROS/NF-κB pathway. Int J Biol Sci. 2017;13(2):145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by Research institute for Convergence of biomedical science and technology (30-2016-014), Pusan National University Yangsan Hospital. The biospecimens and data used for this study were provided by the Biobank of Pusan National University Hospital, a member of the Korea Biobank Network.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Seung Chul Kim or Beum-soo An.

Ethics declarations

Conflict of Interest

Authors do not have conflict of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeong, J.S., Lee, D.H., Lee, JE. et al. The Expression and Contribution of SRCs with Preeclampsia Placenta. Reprod. Sci. 27, 1513–1521 (2020). https://doi.org/10.1007/s43032-020-00142-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-020-00142-5

Keywords

Navigation