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Rapid Effects of Oestrogen on Intracellular Ca2+ in the Uterine Junctional Myometrium of Patients With and Without Adenomyosis in Different Phases of the Menstrual Cycle

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Abstract

We investigated the role of oestrogen receptor 1 (ESR1) in regulating the [Ca2+]i concentration in the junctional zone (JZ) and its effect on adenomyosis. JZ smooth muscle cells (JZSMCs) were isolated from 17 control and 24 adenomyotic uteri, and membrane proteins were extracted from the cells. In the control group, the levels of membrane ESR1 and [Ca2+]i in the proliferative phase were significantly greater than they were in the secretory phase. While no difference was detected between the two phases, ESR1 and [Ca2+]i levels in the adenomyosis group were significantly higher in the proliferative and secretory phases than they were in the control groups. Oestradiol induced a rapid increase in [Ca2+]i in the JZSMCs of both groups. When pretreated with the ESR1 antagonist ICI 182,780, the increase in [Ca2+]i was clearly reduced in both groups compared with the control, but the differences were not significant. Filtered E-6-BSA also induced [Ca2+]i, and its actions were similar to those of oestrogen. Removal of extracellular Ca2+ did not alter the effect of oestradiol, but the phospholipase C inhibitor U73122 (10 μM) and 2-aminoethoxydiphenyl borate (5 μM) significantly reduced the oestradiol-induced [Ca2+]i flux. Oestradiol was unable to induce a [Ca2+]i flux in thapsigargin-depleted cells; this result indicated that oestradiol mediates the [Ca2+]i flux in JZSMCs through ESR1, which activates the phospholipase C pathway. ESR1 levels were assessed by Western blotting. Changes in the [Ca2+]i concentration induced by oestrogen stimulation were analysed by immunofluorescence. The ΔFCa2+ was calculated as the difference between baseline and peak fluorescence response to stimulation. We found that the abnormal intracellular [Ca2+]i response to oestrogen could account for aberrant JZ peristalsis.

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References

  1. Kim JH, Jee BC. Effects of butylparaben supplementation on in vitro development of mouse Preantral follicle. Reprod Sci. 2020;27:1365–71. https://doi.org/10.1007/s43032-020-00159-w.

    Article  PubMed  Google Scholar 

  2. Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):449–63.

    Article  Google Scholar 

  3. Leyendecker G, Kunz G, Noe M, Herbertz M, Mall G. Endometriosis: a dysfunction and disease of the archimetra. Hum Reprod Update. 1998;4(5):752–62.

    Article  CAS  Google Scholar 

  4. Fusi L, Cloke B, Brosens JJ. The uterine junctional zone. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):479–91.

    Article  Google Scholar 

  5. Vedernikov YP, Hartke JR, de Long MA, Saade GR, Garfield RE. Sex hormone effects in non-pregnant rat and human myometrium. Eur J Obstet Gynecol Reprod Biol. 2003;108(1):59–66.

    Article  CAS  Google Scholar 

  6. Abdalla FMF, Maróstica E, Picarelli ZP, Abreu LC, Avellar MCW, Porto CS. Effect of estrogen on muscarinic acetylcholine receptor expression in rat myometrium. Mol Cell Endocrinol. 2004;213(2):139–48.

    Article  CAS  Google Scholar 

  7. Sakamoto K, Kurokawa J. Involvement of sex hormonal regulation of K channels in electrophysiological and contractile functions of muscle tissues. J Pharmacol Sci. 2019;139(4):259–65. https://doi.org/10.1016/j.jphs.2019.02.009.

    Article  CAS  PubMed  Google Scholar 

  8. Patil AS, Swamy GK, Murtha AP, Heine RP, Zheng X, Grotegut CA. Progesterone metabolites produced by cytochrome P450 3A modulate uterine contractility in a murine model. Reprod Sci. 2015;22(12):1577–86. https://doi.org/10.1177/1933719115589414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ezaki K, Motoyama H, Sasaki H. Immunohistologic localization of estrone sulfatase in uterine endometrium and adenomyosis. Obstet Gynecol. 2001;98(5 Pt 1):815–9.

    CAS  PubMed  Google Scholar 

  10. Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. Endometriosis: the pathophysiology as an estrogen-dependent disease. J Steroid Biochem Mol Biol. 2002;83(1–5):149–55.

    Article  CAS  Google Scholar 

  11. Kunz G, Beil D, Huppert P, Leyendecker G. Oxytocin--a stimulator of directed sperm transport in humans. Reprod BioMed Online. 2007;14(1):32–9.

    Article  CAS  Google Scholar 

  12. Han G, Yu X, Lu L, Li S, Ma H, Zhu S, et al. Estrogen receptor alpha mediates acute potassium channel stimulation in human coronary artery smooth muscle cells. J Pharmacol Exp Ther. 2006;316(3):1025–30.

    Article  CAS  Google Scholar 

  13. Castillo C, Ceballos G, Rodríguez D, Villanueva C, Medina R, López J, et al. Effects of estradiol on phenylephrine contractility associated with intracellular calcium release in rat aorta. Am J Phys Cell Phys. 2006;291(6):C1388–C94.

    Article  CAS  Google Scholar 

  14. Kline LW, Karpinski E. Progesterone inhibits gallbladder motility through multiple signaling pathways. Steroids. 2005;70(9):673–9.

    Article  CAS  Google Scholar 

  15. Wang Y-J, Lin M-W, Wu S-N, Sung RJ. The activation by estrogen receptor agonists of the BK(Ca)-channel in human cardiac fibroblasts. Biochem Pharmacol. 2007;73(9):1347–57.

    Article  CAS  Google Scholar 

  16. Raz L, Khan MM, Mahesh VB, Vadlamudi RK, Brann DW. Rapid estrogen signaling in the brain. Neurosignals. 2008;16(2–3):140–53. https://doi.org/10.1159/000111559.

    Article  CAS  PubMed  Google Scholar 

  17. Han G, Ma H, Chintala R, Miyake K, Fulton DJR, Barman SA, et al. Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling. Am J Physiol Heart Circ Physiol. 2007;293(1):H314–H21.

    Article  CAS  Google Scholar 

  18. Aguilar HN, Mitchell BF. Physiological pathways and molecular mechanisms regulating uterine contractility. Hum Reprod Update. 2010;16(6):725–44. https://doi.org/10.1093/humupd/dmq016.

    Article  CAS  PubMed  Google Scholar 

  19. Wang J, Zhang H-h, Duan H. Expression of ERα in endometrial-myometria interface of human adenomyosis. Zhonghua Yi Xue Za Zhi. 2010;90(27):1914–7.

    CAS  PubMed  Google Scholar 

  20. Mehasseb MK, Bell SC, Pringle JH, Habiba MA. Uterine adenomyosis is associated with ultrastructural features of altered contractility in the inner myometrium. Fertil Steril. 2010;93(7):2130–6. https://doi.org/10.1016/j.fertnstert.2009.01.097.

    Article  PubMed  Google Scholar 

  21. Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol. 2001;91(4):1860–7.

    Article  CAS  Google Scholar 

  22. Chaban VV, Mayer EA, Ennes HS, Micevych PE. Estradiol inhibits atp-induced intracellular calcium concentration increase in dorsal root ganglia neurons. Neuroscience. 2003;118(4):941–8.

    Article  CAS  Google Scholar 

  23. Stevis PE, Deecher DC, Suhadolnik L, Mallis LM, Frail DE. Differential effects of estradiol and estradiol-BSA conjugates. Endocrinology. 1999;140(11):5455–8.

    Article  CAS  Google Scholar 

  24. Murray RK, Kotlikoff MI. Receptor-activated calcium influx in human airway smooth muscle cells. J Physiol Lond. 1991;435:123–44.

    Article  CAS  Google Scholar 

  25. Mehasseb MK, Panchal R, Taylor AH, Brown L, Bell SC, Habiba M. Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis. Fertil Steril. 2011;95(7). doi:https://doi.org/10.1016/j.fertnstert.2011.02.051.

  26. Levy M, Mittal K, Chiriboga L, Zhang X, Yee H, Wei J-J. Differential expression of selected gene products in uterine leiomyomata and adenomyosis. Fertil Steril. 2007;88(1):220–3.

    Article  CAS  Google Scholar 

  27. Anamthathmakula P, Kyathanahalli C, Ingles J, Hassan SS, Condon JC, Jeyasuria P. Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy. EBioMedicine. 2019;39:520–30. https://doi.org/10.1016/j.ebiom.2018.11.038.

    Article  PubMed  Google Scholar 

  28. Chaban VV, Lakhter AJ, Micevych P. A membrane estrogen receptor mediates intracellular calcium release in astrocytes. Endocrinology. 2004;145(8):3788–95.

    Article  CAS  Google Scholar 

  29. Montgomery S, Shaw L, Pantelides N, Taggart M, Austin C. Acute effects of oestrogen receptor subtype-specific agonists on vascular contractility. Br J Pharmacol. 2003;139(7):1249–53.

    Article  CAS  Google Scholar 

  30. Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J. The many faces of estrogen signaling. Biochem Med (Zagreb). 2014;24(3):329–42. https://doi.org/10.11613/BM.2014.035.

    Article  Google Scholar 

  31. Tang Z-R, Zhang R, Lian Z-X, Deng S-L, Yu K. Estrogen-receptor expression and function in female reproductive disease. Cells. 2019;8(10). doi:https://doi.org/10.3390/cells8101123.

  32. Li J-J, Duan H, Wang S, Sun F-Q, Gan L, Tang Y-Q, et al. Expression pattern of G-protein-coupled estrogen receptor in myometrium of uteri with and without adenomyosis. Biomed Res Int. 2017;2017:5974693–6. https://doi.org/10.1155/2017/5974693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Paterni I, Bertini S, Granchi C, Macchia M, Minutolo F. Estrogen receptor ligands: a patent review update. Expert Opin Ther Pat. 2013;23(10):1247–71. https://doi.org/10.1517/13543776.2013.805206.

    Article  CAS  PubMed  Google Scholar 

  34. Kunz G, Beil D, Huppert P, Noe M, Kissler S, Leyendecker G. Adenomyosis in endometriosis--prevalence and impact on fertility. Evidence from magnetic resonance imaging. Hum Reprod. 2005;20(8):2309–16.

    Article  CAS  Google Scholar 

  35. Barton M. Position paper: The membrane estrogen receptor GPER--Clues and questions. Steroids. 2012;77(10):935–42. https://doi.org/10.1016/j.steroids.2012.04.001.

    Article  CAS  PubMed  Google Scholar 

  36. Beyer C, Pawlak J, Karolczak M. Membrane receptors for oestrogen in the brain. J Neurochem. 2003;87(3):545–50.

    Article  CAS  Google Scholar 

  37. Bupha-Intr T, Wattanapermpool J. Regulatory role of ovarian sex hormones in calcium uptake activity of cardiac sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol. 2006;291(3):H1101–H8.

    Article  CAS  Google Scholar 

  38. Nett WJ, Oloff SH, McCarthy KD. Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. J Neurophysiol. 2002;87(1):528–37.

    Article  Google Scholar 

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Funding

This work was supported by grants from the Natural Science Foundation of China (No. 81270680) and Beijing Natural Science Foundation (7142056). Additional financial support was provided by Beijing’s municipal administration of hospital clinical medicine and the development of special funding support.

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Authors and Affiliations

  1. Department of Minimally Invasive Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China

    Sha Wang, Hua Duan & Bohan Li

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  1. Sha Wang
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  2. Hua Duan
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  3. Bohan Li
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Contributions

SW performed the laboratory experiments, analysed all the data, and wrote the manuscript; HD developed the project and edited the manuscript; and BHL edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hua Duan.

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Wang, S., Duan, H. & Li, B. Rapid Effects of Oestrogen on Intracellular Ca2+ in the Uterine Junctional Myometrium of Patients With and Without Adenomyosis in Different Phases of the Menstrual Cycle. Reprod. Sci. 27, 1992–2001 (2020). https://doi.org/10.1007/s43032-020-00218-2

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