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  • The most common pathology associated with FGR is poor


    The most common pathology associated with FGR is poor placental perfusion as a result of abnormal placentation [4]. Placental developmental disorders and insufficient hormone synthesis may lead to FGR [5,6]. However, the exact mechanism responsible for abnormal placental development remains unclear. Estrogen-related receptor γ (ERRγ), a member of ERR family, is highly expressed in placenta and other human reproductive tissues [[7], [8], [9]]. ERRγ is expressed at very higher levels during vascularization of the placenta during pregnancy [8,10]. Moreover, during human trophoblast differentiation, ERRγ has an O2-dependent regulatory role [10]. In our previous study, aberrant expression of ERRγ was found to potentially contribute to the pathogenesis of preeclampsia [11]. Furthermore, since preeclampsia and FGR are both diseases with placental origins, abnormal hormone synthesis or inadequate development of uterine spiral RITA may cause these disorders. Therefore, we hypothesize that aberrant ERRγ expression may also lead to placental insufficiency, thereby contributing to the development of FGR. Hydroxysteroid (17β) dehydrogenase type 1 (HSD17B1) is a member of the 17β-hydroxysteroid dehydrogenase family and is a steroidogenic enzyme that catalyzes the conversion of estrone (E1) from its inactive form to its active 17β-estradiol (E2) form [12]. HSD17B1 has been extensively studied in estrogen-dependent diseases and has been found to promote cell growth by stimulating E2 synthesis [13,14]. HSD17B1 also plays an important role during pregnancy. For example, the rs605059 polymorphism of HSD17B1 is associated with an increased risk of recurrent spontaneous abortion [15]. Production of 17β-estradiol is catalyzed by HSD17B1, and 17β-estradiol then acts via estrogen receptor (ER) α to mediate a positive feedback action on human syncytiotrophoblast differentiation [16]. We previously observed that when ERRγ was knocked down in syncytiotrophoblast cells, HSD17B1 was subsequently down-regulated [17]. However, the roles of ERRγ and HSD17B1 in the pathogenesis of FGR remain unknown. Therefore, the aim of this study was to investigate the expression profiles of ERRγ and HSD17B1 in placenta tissues affected by FGR and to examine a possible molecular mechanism by which ERRγ is able to regulated HSD17B1 RITA during development of FGR.
    Materials and methods
    Discussion Normal placental development is dependent on hormone synthesis, trophoblast invasion, and remodeling of maternal uterine decidual spiral arteries [21]. Dysfunction of a placenta can lead to pregnancy-specific diseases such as preeclampsia and FGR [22,23]. Therefore, to explore the pathogenesis of FGR, it is critical to study the expression profiles of varies genes and/or proteins in placenta tissue. In the present study, mRNA and protein expression levels of ERRγ were found to be significantly lower in the FGR placenta tissues. These results are consistent with those of a recent study where lower levels of ERRγ expression were also observed in FGR placentae [24]. The latter study did not further investigate the role of ERRγ in the pathogenesis of FGR. Besides we found that mRNA and protein levels of HSD17B1 decreased in FGR placentae. To our knowledge, this is the first study to demonstrate an association between HSD17B1 and ERRγ in FGR placentae. ERRγ is selectively expressed in metabolically active and highly vascularized tissues such as heart, kidney, skeletal muscle, and placenta [25,26]. In recent years, accumulating evidence has indicated that ERRγ plays a crucial role in tumor cell invasion and proliferation [[27], [28], [29]]. As the similarities of the invasion, proliferation, and angiogenesis capacity between extravillous trophoblasts and tumor cells [30], we speculate that ERRγ may play an important role in FGR development by regulating the invasion and proliferation of trophoblasts. To verify this hypothesis, invasion assays and proliferation assays were performed. Knockdown of ERRγ was found to inhibit the invasive phenotype and proliferation of the transfected trophoblast cells. Thus, down-regulation of ERRγ appears to influence the differentiation of human syncytiotrophoblasts and invasion and proliferation of cytotrophoblasts, thereby leading to dysfunction of uterine spiral artery remodeling and poor placental perfusion [4] and further contributing to the pathogenesis of FGR.