Abstract
The aim of this study was to analyze the expression of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RxRα), a binding heterodimer playing a pivotal role in the successful trophoblast invasion, in the placental tissue of preeclamptic patients. Furthermore, we aimed to characterize a possible interaction between PPARγ and H3K4me3 (trimethylated lysine 4 of the histone H3), respectively H3K9ac (acetylated lysine 9 of the histone H3), to illuminate the role of histone modifications in a defective trophoblast invasion in preeclampsia (PE). Therefore, the expression of PPARγ and RxRα was analyzed in 26 PE and 25 control placentas by immunohistochemical peroxidase staining, as well as the co-expression with H3K4me3 and H3K9ac by double immunofluorescence staining. Further, the effect of a specific PPARγ-agonist (Ciglitazone) and PPARγ-antagonist (T0070907) on the histone modifications H3K9ac and H3K4me3 was analyzed in vitro. In PE placentas, we found a reduced expression of PPARγ and RxRα and a reduced co-expression with H3K4me3 and H3K9ac in the extravillous trophoblast (EVT). Furthermore, with the PPARγ-antagonist treated human villous trophoblast (HVT) cells and primary isolated EVT cells showed higher levels of the histone modification proteins whereas treatment with the PPARγ-agonist reduced respective histone modifications. Our results show that the stimulation of PPARγ-activity leads to a reduction of H3K4me3 and H3K9ac in trophoblast cells, but paradoxically decreases the nuclear PPARγ expression. As the importance of PPARγ, being involved in a successful trophoblast invasion has already been investigated, our results reveal a pathophysiologic connection between PPARγ and the epigenetic modulation via H3K4me3 and H3K9ac in PE.
Highlights
Affecting around five percent of all pregnancies, preeclampsia (PE) represents one of the most frequent gestational diseases [1] and a relevant cause for maternal deaths [2,3,4]
The aim of this study was to analyze the expression of peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RxRα), a binding heterodimer playing a pivotal role in the successful trophoblast invasion, in the placental tissue of preeclamptic patients
As ineffective trophoblast invasion represents a pivotal element of the path3oopf 2h0ysiology of PE, the aim of this study was to analyze the expression of PPARγ and RxRα, especially in the extravillous trophoblast (EVT) in the placenta of preeclamptic patients, and to characterize a possible association between the histone modifications found to be decreased in the placenta duringtthhPeeErh.aipsteounteicmtaordgiefit.caTthioenrsefHor3eK, 4amfuer3thanerdiHnv3eKs9tiagcactoiounldofbePPilAluRmyinaantdintgherecgoanrdneincgtiothnewraipthy possibilities of PE
Summary
Affecting around five percent of all pregnancies, preeclampsia (PE) represents one of the most frequent gestational diseases [1] and a relevant cause for maternal deaths [2,3,4]. Impaired trophoblast invasion [15], impaired remodeling of spiral arteries [5,16], and defective placentation [13,17,18,19] contribute to the aforementioned placental insufficiency. Considering placental maturing, it is necessary to distinguish between the development of the placental villi (cytotrophoblast proliferation, syncytial fusion) [20] and the trophoblast invasion happening simultaneously to the vascular remodeling [21,22]. All trophoblasts, which reside outside the placental villi are summarized under the term EVT [21] These trophoblasts migrate together with uteroplacental arteries into the decidua, and it is already known that several instances, such as trophoblast apoptosis, lead to a defective trophoblast invasion in PE [23,24,25]
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