The expression and activation of sex steroid receptors in the preeclamptic placenta

Park,Mee‑Na; Park,Kyung‑Hee; Lee,Jae‑Eon; Shin,Ye  Young; An,Sung‑Min; Kang,Seong  Soo; Cho,Wan‑Seob; An,Beum‑Soo; Kim,Seung  Chul

doi:10.3892/ijmm.2018.3474

The expression and activation of sex steroid receptors in the preeclamptic placenta

Authors:
- Mee‑Na Park
- Kyung‑Hee Park
- Jae‑Eon Lee
- Ye Young Shin
- Sung‑Min An
- Seong Soo Kang
- Wan‑Seob Cho
- Beum‑Soo An
- Seung Chul Kim
View Affiliations

Affiliations: Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Gyeongsangnam‑do 627‑706, Republic of Korea, Department of Pediatrics, Biomedical Research Institute, Pusan National University School of Medicine, Busan 302‑739, Republic of Korea, Department of Veterinary Surgery, College of Veterinary Medicine, Chonnam National University, Gwangju 500‑757, Republic of Korea, Department of Medical Biotechnology, School of Natural Resources and Life Science, Dong‑A University, Busan 604‑714, Republic of Korea, Department of Obstetrics and Gynecology, Biomedical Research Institute, Pusan National University School of Medicine, Busan 302‑739, Republic of Korea
Published online on: February 8, 2018 https://doi.org/10.3892/ijmm.2018.3474
Pages: 2943-2951

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Estrogen and progesterone are the main pregnancy hormones produced by the placenta. It is well understood that estrogen stimulates angiogenesis in the uterus during the reproductive cycle. Although the estrogen and progesterone signaling pathways are assumed to be associated with placental vascularization and preeclampsia, expression of estrogen receptors (ESRs) and progesterone receptor (PGR) in the placenta have not been well studied. The present study examined the expression patterns of steroid hormone receptors in placentas. Human placenta samples were collected and divided into normal and preeclampsia groups. Results revealed that expression levels of ESR1 were reduced, whereas ESR2 and PGR were elevated in preeclamptic placentas. To generate an in vitro preeclampsia environment, human placenta‑derived BeWo cells were incubated under hypoxic conditions, or treated with catechol‑O‑methyl transferase inhibitor (COMT‑in) or L‑NG‑nitroarginine methyl ester (L‑NAME). Expression levels of ESR1, ESR2 and PGR in hypoxic cells demonstrated similar regulation as those in placentas from women with preeclampsia. Although COMT‑in and L‑NAME did not significantly regulate the expression levels of the receptors, COMT‑in translocated ESR2 and PGR from the nucleus to the cytoplasm, indicating that these receptors were inactivated. These results suggested that ESRs and PGR are associated with symptoms of preeclampsia in the placenta. The expression of ESR1 was reduced in preeclamptic placenta and hypoxic BeWo cells. In addition, the activation of ESR2 and PGR was blocked in placenta cells subjected to COMT‑in treatment. The reduced ESR1 expression and inactivation of ESR2 and PGR proteins may affect the physiological complications of preeclampsia in the placenta.

View Figures

View References

1	Barker DJ: The fetal origins of coronary heart disease. Acta Paediatr Suppl. 422:78–82. 1997. View Article : Google Scholar : PubMed/NCBI
2	Cockell AP and Poston L: Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension. 30:247–251. 1997. View Article : Google Scholar : PubMed/NCBI
3	Jobe SO, Tyler CT and Magness RR: Aberrant synthesis, metabolism, and plasma accumulation of circulating estrogens and estrogen metabolites in preeclampsia implications for vascular dysfunction. Hypertension. 61:480–487. 2013. View Article : Google Scholar : PubMed/NCBI
4	Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 350:672–683. 2004. View Article : Google Scholar : PubMed/NCBI
5	VanWijk MJ, Kublickiene K, Boer K and VanBavel E: Vascular function in preeclampsia. Cardiovasc Res. 47:38–48. 2000. View Article : Google Scholar : PubMed/NCBI
6	Furuya M, Kurasawa K, Nagahama K, Kawachi K, Nozawa A, Takahashi T and Aoki I: Disrupted balance of angiogenic and antiangiogenic signalings in preeclampsia. J Pregnancy. 2011:1237172011. View Article : Google Scholar : PubMed/NCBI
7	Staun-Ram E and Shalev E: Human trophoblast function during the implantation process. Reprod Biol Endocrinol. 3:562005. View Article : Google Scholar : PubMed/NCBI
8	Pennington KA, Schlitt JM, Jackson DL, Schulz LC and Schust DJ: Preeclampsia: Multiple approaches for a multifacto-rial disease. Dis Model Mech. 5:9–18. 2012. View Article : Google Scholar : PubMed/NCBI
9	Genbacev O, Joslin R, Damsky CH, Polliotti BM and Fisher SJ: Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest. 97:540–550. 1996. View Article : Google Scholar : PubMed/NCBI
10	Dekker GA and Sibai BM: Low-dose aspirin in the prevention of preeclampsia and fetal growth retardation: Rationale, mechanisms, and clinical trials. Am J Obstet Gynecol. 168:214–227. 1993. View Article : Google Scholar : PubMed/NCBI
11	Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J and Smith D; Magpie Trial Collaboration Group: Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: A randomised placebo-controlled trial. Lancet. 359:1877–1890. 2002. View Article : Google Scholar : PubMed/NCBI
12	Sibai B, Dekker G and Kupferminc M: Pre-eclampsia. Lancet. 365:785–799. 2005. View Article : Google Scholar : PubMed/NCBI
13	Witlin AG and Sibai BM: Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol. 92:883–889. 1998.PubMed/NCBI
14	Björnström L and Sjöberg M: Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 19:833–842. 2005. View Article : Google Scholar : PubMed/NCBI
15	Chen JZ, Sheehan PM, Brennecke SP and Keogh RJ: Vessel remodelling, pregnancy hormones and extravillous trophoblast function. Mol Cell Endocrinol. 349:138–144. 2012. View Article : Google Scholar
16	Açıkgöz Ş, Bayar UO, Can M, Güven B, Mungan G, Doğan S and Sümbüloğlu V: Levels of oxidized LDL, estrogens, and progesterone in placenta tissues and serum paraoxonase activity in preeclampsia. Mediators Inflamm. 2013:8629822013. View Article : Google Scholar
17	Feng Y, Zhang P, Zhang Z, Shi J, Jiao Z and Shao B: Endocrine disrupting effects of triclosan on the placenta in pregnant rats. PLoS One. 11:e01547582016. View Article : Google Scholar : PubMed/NCBI
18	Albrecht ED and Pepe GJ: Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy. Int J Dev Biol. 54:397–408. 2010. View Article : Google Scholar :
19	Magness RR: Maternal cardiovascular and other physiologic responses to the endocrinology of pregnancy. Endocrinol Pregnancy. 9:507–539. 1998. View Article : Google Scholar
20	Magness RR and Rosenfeld CR: Local and systemic estradiol-17 beta: Effects on uterine and systemic vasodilation. Am J Physiol. 256:E536–E542. 1989.PubMed/NCBI
21	Reynolds LP, Kirsch JD, Kraft KC, Knutson DL, McClaflin WJ and Redmer DA: Time-course of the uterine response to estradiol-17beta in ovariectomized ewes: Uterine growth and microvascular development. Biol Reprod. 59:606–612. 1998. View Article : Google Scholar : PubMed/NCBI
22	Szekeres-Bartho J: Immunosuppression by progesterone in pregnancy. CRC Press; pp. 1–155. 1992
23	Buhimschi I, Yallampalli C, Chwalisz K and Garfield RE: Pre-eclampsia-like conditions produced by nitric oxide inhibition: Effects of L-arginine, D-arginine and steroid hormones. Hum Reprod. 10:2723–2730. 1995. View Article : Google Scholar : PubMed/NCBI
24	Ito M, Nakamura T, Yoshimura T, Koyama H and Okamura H: The blood pressure response to infusions of angiotensin II during normal pregnancy: Relation to plasma angiotensin II concentration, serum progesterone level, and mean platelet volume. Am J Obstet Gynecol. 166:1249–1253. 1992. View Article : Google Scholar : PubMed/NCBI
25	Liao QP, Buhimschi IA, Saade G, Chwalisz K and Garfield RE: Regulation of vascular adaptation during pregnancy and post-partum: Effects of nitric oxide inhibition and steroid hormones. Hum Reprod. 11:2777–2784. 1996. View Article : Google Scholar : PubMed/NCBI
26	Radwanska E: The role of reproductive hormones in vascular disease and hypertension. Steroids. 58:605–610. 1993. View Article : Google Scholar : PubMed/NCBI
27	Dodd JM, Jones L, Flenady V, Cincotta R and Crowther CA: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev. CD0049472013.PubMed/NCBI
28	Hass DM and Ramsey PS: Progestogen for preventing miscarriage. Cochrane Database Syst Rev. CD0035112008.
29	Meher S and Duley L: Interventions for preventing pre-eclampsia and its consequences: Generic protocol. Cochrane Libr. CD0053012005.
30	Jones HN, Ashworth CJ, Page KR and McArdle HJ: Cortisol stimulates system A amino acid transport and SNAT2 expression in a human placental cell line (BeWo). Am J Physiol Endocrinol Metab. 291:E596–E603. 2006. View Article : Google Scholar : PubMed/NCBI
31	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
32	Carty DM, Delles C and Dominiczak AF: Novel biomarkers for predicting preeclampsia. Trends Cardiovasc Med. 18:186–194. 2008. View Article : Google Scholar : PubMed/NCBI
33	Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T and Shibuya M: Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res. 61:1207–1213. 2001.PubMed/NCBI
34	Ahmed A, Dunk C, Ahmad S and Khaliq A: Regulation of placental vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) and soluble Flt-1 by oxygen-a review. Placenta. 21(Suppl A): S16–S24. 2000. View Article : Google Scholar
35	McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ and McClure N: Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol. 191:1240–1246. 2004. View Article : Google Scholar : PubMed/NCBI
36	Yin G, Zhu X, Guo C, Yang Y, Han T, Chen L, Yin W, Gao P, Zhang H, Geng J, et al: Differential expression of estradiol and estrogen receptor α in severe preeclamptic pregnancies compared with normal pregnancies. Mol Med Rep. 7:981–985. 2013. View Article : Google Scholar : PubMed/NCBI
37	Schiessl B, Mylonas I, Hantschmann P, Kuhn C, Schulze S, Kunze S, Friese F and Jeschke U: Expression of endothelial NO synthase, inducible NO synthase, and estrogen receptors alpha and beta in placental tissue of normal, preeclamptic, and intrauterine growth-restricted pregnancies. J Histochem Cytochem. 53:1441–1449. 2005. View Article : Google Scholar : PubMed/NCBI
38	Manoranjan B, Salehi F, Scheithauer BW, Rotondo F, Kovacs K and Cusimano MD: Estrogen receptors alpha and beta immunohistochemical expression: Clinicopathological correlations in pituitary adenomas. Anticancer Res. 30:2897–2904. 2010.PubMed/NCBI
39	Nevo O, Soleymanlou N, Wu Y, Xu J, Many A, Zamudio S and Caniggia I: Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1. Am J Physiol Regul Integr Comp Physiol. 291:R1085–R1093. 2006. View Article : Google Scholar : PubMed/NCBI
40	Soleymanlou N, Jurisica I, Nevo O, Ietta F, Zhang X, Zamudio S, Post M and Caniggia I: Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab. 90:4299–4308. 2005. View Article : Google Scholar : PubMed/NCBI
41	Babbedge RC, Bland-Ward PA, Hart SL and Moore PK: Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br J Pharmacol. 110:225–228. 1993. View Article : Google Scholar : PubMed/NCBI
42	Pertegal M, Fenoy FJ, Hernández M, Mendiola J, Delgado JL, Bonacasa B, Corno A, López B, Bosch V and Hernández I: Fetal Val108/158Met catechol-O-methyltransferase (COMT) polymorphism and placental COMT activity are associated with the development of preeclampsia. Fertil Steril. 105:134–143. e1–e3. 2016. View Article : Google Scholar
43	Kanasaki K, Palmasten K, Sugimoto H, Ahmad S, Hamano Y, Xie L, Parry S, Augustin SH, Gattone VH, Folkman J, et al: Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature. 453:1117–1121. 2008. View Article : Google Scholar : PubMed/NCBI
44	Yallampalli C and Garfield RE: Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia. Am J Obstet Gynecol. 169:1316–1320. 1993. View Article : Google Scholar : PubMed/NCBI
45	Beato M: Gene regulation by steroid hormones. Cell. 56:335–344. 1989. View Article : Google Scholar : PubMed/NCBI