Although an inflammatory microenvironment is required for successful implantation, an inflammatory overreaction is one of the causes of unexplained recurrent pregnancy losses (uRPL). Prostaglandin E2 (PGE2) plays a pivotal role in regulating immune balance during early pregnancy, and it can stimulate inflammatory reactions via prostaglandin E2 receptor 3 (EP3). However, the role of PGE2 receptor signaling in the uRPL remains unknown. We aimed to investigate whether EP3 signaling is involved in the mechanism of uRPL. Via immunohistochemistry we could show that the expression of cyclooxygenase-2, EP3 and G protein alpha inhibitor 1 (Gi1) was enhanced in the decidua of the uRPL group in comparison to the control group in first-trimester placentas. In vitro, we demonstrated that sulprostone (an EP1/EP3 agonist) inhibited the secretion of beta-hCG and progesterone in JEG-3 cells and the secretion of beta-hCG in HTR-8/SVneo cells while it induced the expression of plasminogen activator inhibitor type 1 in JEG-3 cells. In addition, PGE2/sulprostone was able to stimulate the expression of Gi1, phosphorylated-extracellular signal-regulated kinases 1/2 (p-ERK1/2) and p53. L-798,106 (an EP3-specific antagonist) suppressed the expression of EP3 and p-ERK1/2 without affecting the secretion of beta-hCG. Elevated activation of EP3 signaling in first-trimester placentas plays an important role in regulating the inflammatory microenvironment, the hormone secretion of extravillous trophoblasts and the remodeling of extracellular matrix in the fetal-maternal interface. L-798,106 might be a ‘potential therapeutic candidate’ for the treatment of uRPL.
Yao Ye, Aurelia Vattai, Nina Ditsch, Christina Kuhn, Martina Rahmeh, Sven Mahner, Myriam Ripphahn, Roland Immler, Markus Sperandio, Udo Jeschke and Viktoria von Schönfeldt
Michael J Gratz, Stavroula Stavrou, Christina Kuhn, Simone Hofmann, Kerstin Hermelink, Helene Heidegger, Stefan Hutter, Doris Mayr, Sven Mahner, Udo Jeschke and Aurelia Vattai
l-dopa decarboxylase (DDC) is responsible for the synthesis of dopamine. Dopamine, which binds to the D2-dopamine receptor (D2R), plays an important role in the maintenance of pregnancy. Aim of our study was the analysis of DDC and D2R expression in placentas of spontaneous miscarriages (SMs) and recurrent miscarriages (RMs) in comparison to healthy controls.
Patients with SM (n = 15) and RM (n = 15) were compared with patients from healthy pregnancies (n = 15) (pregnancy weeks 7–13 each). Placental tissue has been collected from SMs and RMs from the first trimester (Department of Gynaecology and Obstetrics, LMU Munich) and from abruptions (private practice, Munich). Placental cell lines, BeWo- and JEG-3 cells, were stimulated with the trace amines T0AM and T1AM in vitro.
Levels of DDC and D2R in trophoblasts and the decidua were lower in RMs in comparison to healthy controls. Stimulation of BeWo cells with T1AM significantly reduced DDC mRNA and protein levels. Via double-immunofluorescence, a DDC-positive cell type beneath decidual stromal cells and foetal EVT in the decidua could be detected.
Downregulation of DDC and D2R in trophoblasts of RMs reflects a reduced signal cascade of catecholamines on the foetal side.
Stavroula Stavrou, Michael Gratz, Eileen Tremmel, Christina Kuhn, Simone Hofmann, Helene Heidegger, Mina Peryanova, Kerstin Hermelink, Stefan Hutter, Bettina Toth, Doris Mayr, Sven Mahner, Udo Jeschke and Aurelia Vattai
Thyroid hormones play an important role in the maintenance of pregnancy. Their derivates, endogenous amines, act via binding to the trace amine-associated receptor (TAAR1). The aim of our study was to analyse the regulation of TAAR1, serine/threonine kinase (pGSK3β) and ornithine decarboxylase (ODC) in placentas of healthy pregnancies, spontaneous (SM) and recurrent miscarriages (RM) and to investigate the influence of thyroid hormone derivates on TAAR1 expression in trophoblast model cells in vitro.
Patients with SM (n = 15) and RM (n = 15) were compared with patients with healthy pregnancies (n = 15) (pregnancy weeks 7–13 each). Immunohistochemistry was applied to analyse placental TAAR1, pGSK3β and ODC expression. Protein expression of the receptors after stimulation with T3, T1AM and RO5203548 in BeWo trophoblast model cells was determined via Western blot. Double-immunofluorescence was used to determine placental expression of TAAR1 and ODC.
Levels of TAAR1, pGSK3β and ODC were higher in placentas of RM in comparison to healthy controls. Stimulation of BeWo cells with T3, T1AM and RO5203548 significantly increased TAAR1 expression. ODC expression in BeWo cells was upregulated through T3. Via double-immunofluorescence, TAAR1 and ODC-positive EVT could be detected.
Upregulation of placental TAAR1 may indicate an increased decarboxylation of thyroid hormones in miscarriages. Patients with RM may have a lack of T3 through an enhanced transformation of T3 into T1AM induced by the ODC. Future investigations could be carried out to analyse what role a prophylactic T3 substitution plays for patients.