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Reduced ELABELA Expression Attenuates Trophoblast Invasion Through the PI3K/AKT/Mtor Pathway in Early Onset Preeclampsia T

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Reduced ELABELA Expression Attenuates Trophoblast Invasion Through the PI3K/AKT/Mtor Pathway in Early Onset Preeclampsia T Placenta 87 (2019) 38–45 Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta Reduced ELABELA expression attenuates trophoblast invasion through the PI3K/AKT/mTOR pathway in early onset preeclampsia T Lijing Wanga,b, Yan Zhangc, Hongmei Qud, Fengsen Xub, Haiyan Hub, Qian Zhangb, ∗ Yuanhua Yea,c, a Department of Obstetrics and Gynecology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266000, China b Department of Obstetrics, Qingdao Municipal Hospital, Qingdao, 266000, China c Department of Obstetrics, Affiliated Hospital of Qingdao University, Qingdao, 266000, China d Department of Obstetrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, China ARTICLE INFO ABSTRACT Keywords: Introduction: Early onset preeclampsia is linked to abnormal trophoblast invasion, leading to insufficient re- ELA casting of uterine spiral arteries and shallow placental implantation. This study investigated ELABELA (ELA) PI3K expression and its involvement in the pathogenesis of early onset preeclampsia. AKT Methods: We used immunohistochemistry, quantitative PCR and Western blot to calculate ELA levels in the Invasion placentas. Transwell assays were utilize to assess the invasion and migration of trophoblastic Cells. Western blot Preeclampsia was used to identify the concentrations of vital kinases in PI3K/AKT/mTOR pathways and invasion-related proteins in trophoblast cells. Results: ELA was expressed in villous cytotrophoblasts and syncytiotrophoblasts in placental tissue. Compared with the normal pregnancies, ELA mRNA and protein expression was significantly reduced in early onset pre- eclampsia placentas. In the HTR-8/SVneo cells, when ELA was knocked down, the invasion and migration capability of cells decreased significantly, with MMP2 and MMP9 expression downregulated and the expression of important kinases in the PI3K/AKT/mTOR pathways being significantly decreased compared to the control group. Overexpression of ELA was on the contrary. Besides, while PI3K was blocked, the invasion and migration capability of HTR-8/SVneo cells and the expression of key kinases in PI3K/AKT/mTOR pathways were decreased significantly. Discussion: ELA stimulates the invasion and migration of trophoblastic cells through activation of downstream PI3K/AKT/mTOR pathway and is complicit in early onset preeclampsia pathogenesis. Our research offers a potential novel treatment for PE. 1. Introduction maternal complications and adverse perinatal consequences [8,9]. It is largely thought that insufficient infiltration of trophoblast cells and Preeclampsia (PE) is a serious systemic disease occurring during disordered remodeling of the uterine spiral artery can lead to superficial pregnancy in which proteinuria and hypertension are observed after 20 placental implantation, causing insufficient uterine and placental blood weeks of pregnancy. The incidence rate of preeclampsia is approxi- flow that leads to early onset preeclampsia [10–12]. The migration and mately 3%–8% annually [1–3]. It is a serious complication that en- invasion of trophoblastic cells are influenced by multiple factors and dangers the health of both the mother and child [3–5]. Preeclampsia is the precise molecular mechanisms underlying the pathogenesis of the a multifactorial disease that is caused by maternal, fetal and environ- disease remain unclear. mental factors without an effective treatment at present, although the ELA, also known as Apela or Toddler, is a recently discovered 54 pathogenesis remains unclear. Early onset preeclampsia was proposed amino acid peptide hormone which binds and activates the APJ re- by European and American researchers in the 1980s as a disease ceptor. ELA is highly conserved among different species, suggesting that manifesting before 34 weeks of gestation [6,7]. This form of the disease it is a key regulator of essential physiological functions [13,14]. It is has attracted much attention due to its potential for causing severe known to be involved in the development of zebrafish embryos via ∗ Corresponding author. Department of Obstetrics, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China. E-mail address: [email protected] (Y. Ye). https://doi.org/10.1016/j.placenta.2019.08.077 Received 9 March 2019; Received in revised form 22 July 2019; Accepted 7 August 2019 0143-4004/ © 2019 Published by Elsevier Ltd. L. Wang, et al. Placenta 87 (2019) 38–45 promotion of APJ receptor signaling-mediated endoderm differentia- repeatedly rinsed with cold phosphate buffered saline (PBS), with one tion [13,14]. ELA regulates mammalian circulation and embryonic piece placed in formaldehyde for immunohistochemistry and another development [15]. Human ELA is detectable in adult kidneys, prostate quickly frozen and maintained at −80 °C until required for subsequent and embryonic stem cells in addition to placental tissue [13,16]. The RNA and protein extraction. ELA/APJ axis can effectively protect the heart and kidneys, and induces – vasodilation in adults [17 19]. ELA promotes the growth and self-re- 2.2. Cell culture, RNA interference and transfection with plasmids newal of human embryonic stem cells via activation of the PI3K/Akt pathway [16]. ELA has a critical role in the development of the placenta Human HTR-8/SVneo first trimester cytotrophoblast cells [39] were and heart and promotes angiogenesis during embryonic development acquired from the Chinese Academy of Sciences in Shanghai. Cells were fi [20,21]. It has been reported that Elabela-de cient mice develop pre- cultured in DMEM (Invitrogen, USA) containing 10% FBS plus peni- eclampsia [22], suggesting it has a role in the pathogenesis of pre- cillin/streptomycin and maintained at 37 °C in an atmosphere con- eclampsia, but the specific mechanism remains unknown. taining 5% CO2. ELA is highly expressed in human placental trophoblasts. The pla- Small interfering RNA (siRNA) sequences used in this study were centa lacks innervation [23]. Both ELA and APJ have been found to be transfected into cells for 24 h, in accordance with the manufacturer's simultaneously expressed in the placenta, suggestive of potential au- protocol (Shanghai GenePharma Co., Ltd, Shanghai, China). siRNA se- tocrine regulation of placental memory via the ELA/APJ pathway. quences were as follows. Targeting ELA (siRNA-ELA-sense: 5′-GUGAU fi Exogenous ELA has also been shown to signi cantly increase the in- UCUCGUGCCUCAACTT-3'; siRNA-ELA-antisense: 5′-GUUGAGGCACGA ff vasiveness of trophoblasts, suggesting that ELA has a paracrine e ect on GAAUCACTG-3′) and control siRNA (scramble-sense; 5′-GAGUGGGUC ff trophoblast di erentiation [20]. ELA can induce cell invasion through UGGGUCUUCCCGTT-3'; scramble-antisense; 5′-CGGGAA GACCCAGAC both autocrine and paracrine signaling and may promote subsequent CCACUCTG-3′). spiral artery reconstruction that prevents the development of pre- HTR-8/SVneo cells were transfected with over-expressed ELA or fi eclampsia [20], although further research is required to con rm the blank control plasmids for 24 h following the manufacturer's protocols underlying mechanisms. (Shanghai GenePharma Co., Ltd, Shanghai, China). Many investigations have demonstrated that the PI3K/AKT pathway is involved in the pathogenesis of preeclampsia [24,25], with ab- normalities being implicated in the abnormal development of the pla- 2.3. Histology, H&E staining and immunohistochemical analysis cental labyrinth [26,27]. Downregulation of p-AKT in extravillous tro- phoblasts affects trophoblast proliferation and invasion [28]. Together, Polyclonal antibodies against ELA were produced as previously these observations suggest that the PI3K/AKT pathway is involved in described [13] by BGI, Beijing, China. The placental tissue samples fi ffi trophoblast invasion, performing an important role in preeclampsia. were cut into 5 mm pieces, xed in formaldehyde, para n embedded, It is generally accepted that cell invasion and migration are closely dewaxed in xylene, then hydrated through a rising gradient of alcohol related to the activity of the two proteases, matrix metalloproteinase-2 concentrations. (MMP-2) and matrix metalloproteinase-9 (MMP-9) [29–31]. Both MMP- H&E staining: Some sections were stained with hematoxylin, blue 2 and MMP-9 promote cell invasion by degrading collagen type IV color developed in ammonia water, dyed with eosin, then dehydrated, [32,33], the principal component of the extracellular matrix and basal cleared, sealed with neutral gum then observed using light microscopy. membrane of the endometrium [34 ,35], and are proteases closely re- Antigens were retrieved by boiling unstained sections in citrate ff lated to trophoblast invasion [36–38]. bu er then cooling naturally. Endogenous peroxidase activity was ter- In this study we aimed to study the hypothesis that ELA plays a role minated by incubating sections at room temperature for 10 min in 3% in the mechanism of trophoblast invasion and migration through the hydrogen peroxide. A polyclonal rabbit anti-human ELA antibody (di- PI3K/AKT/mTOR pathway. To test this hypothesis, the expression of lution 1:200) was used as a primary antibody to stain sections overnight ELA in placental villi was measured and then ELA expression in the at 4 °C. A Goat anti rabbit antibody was then added as a secondary placentas of women with early onset preeclampsia was compared with antibody (dilution 1:10,000, Cell Signaling Technology, Danvers, MA, that in healthy pregnant women. Finally, the
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