Retinoid X receptor α and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages

Abstract

The retinoid X receptor a (RXRa) is a nuclear hormone receptor that is able to bind other nuclear receptors in a heterodimeric complex, thereby activating gene transcription. Recently, we identified enhanced expression of RXRa in extravillous trophoblasts (EVT) and villous trophoblasts (VT) of miscarried placentas. In addition, an increased number of apoptotic EVT was present in miscarried placentas. In this study, on the basis of immunocytochemical analysis, western blots, and quantitative real-time reverse transcription PCR, we could demonstrate a reduced expression of RXRa in choriocarcinoma cell lines and in human VTs after stimulation with the retinoids 9-cis-retinoic acid and all-transretinoic acid and the prostaglandin 15-deoxy-D 12,14 -prostaglandin J 2 . Furthermore, a simultaneous expression of RXRa and the apoptotic marker M30 CytoDEATH in EVT of miscarried placentas from the first trimester was shown. In EVT of control placentas from legal termination of pregnancies, no co-expression of RXRa and M30 could be detected. A likely conclusion is that RXRa plays an important role in the induction of apoptosis. Downregulation of RXRa, as observed in the tested choriocarcinoma cells and trophoblasts, might serve as a protection against apoptosis and miscarriage. In conclusion, RXRa represents a potential target in the treatment of recurrent miscarriages.

PPARgamma Expression is Diminished in Macrophages of Recurrent Miscarriage Placentas

“…Already decades ago, the natural binding partner of PPAR, the RXR was described in this trophoblast compartment: RAR and RXR, both types of receptors were present in the proliferative intermediate villous trophoblast [33]. Later, RXR was found to play a crucial role in pregnancy and is a key regulator of apoptosis in trophoblasts of patients with recurrent miscarriages [9]. PPAR on the other hand was also described to be dysregulated in different trophoblast compartments of the miscarriage placenta [34,35], although PPAR expression in the IVT was never investigated before.…”

“…PPAR together with its heterodimer binding partner retinoid X receptor  (RXR) are involved in cell proliferation, cell differentiation, and organogenesis [8]. RXR is upregulated in extravillous trophoblast in recurrent miscarriages in humans [9]. RXR plays a pivotal role in the receptor family, due to its ability to form heterodimers with other nuclear receptors.…”

“…peroxisome proliferatoractivated receptor (PPAR), thyroid hormone receptor (TR), and liver X receptor (LXR) [2,[10][11][12]. Especially the expression of the isoform PPAR is linked to trophoblast invasion [13] and downregulation of the isoform RXRα seems to protect from apoptosis in human trophoblasts [9].…”

RXRα is upregulated in first trimester endometrial glands of spontaneous abortions unlike LXR and PPARγ

“…The nuclear retinoid X receptor (RXR), which is involved in cell proliferation, cell differentiation, and organogenesis, 2 is upregulated in extravillous trophoblast in recurrent miscarriages in humans. 3 RXR plays a pivotal role in the receptor family, due to its ability to form heterodimers with other nuclear receptors. Heterodimer partners are e.g.…”

“…4-6 Especially the expression of the isoform PPARγ is linked to trophoblast invasion 7-9 and downregulation of the isoform RXRα seems to protect against apoptosis in human trophoblasts. 3 LXR is a physiological regulator of lipid and cholesterol metabolism and inflammation, 10 of trophoblast invasion and maternal-fetal cholesterol transport. 11,12 These nuclear receptors are crucially involved in maintaining a viable pregnancy, their role had been clarified especially in human trophoblastic tissue: Toth et al showed that extravillous trophoblast (EVT) in placentas of miscarriages show a significantly higher expression of RXRα in comparison to EVT in placentas of elective termination of healthy pregnancies.…”