Endoplasmic reticulum stress impairs trophoblast syncytialization through upregulation of HtrA4 and causes early-onset preeclampsia

作者全名："Yuan, Xi; Liu, Xiyao; Zhu, Fangyu; Huang, Biao; Lin, Li; Huang, Jiayu; Wen, Li; Kilby, Mark D.; Baker, Philip N.; Fu, Yong; Wu, Weiwei; Qi, Hongbo; Tang, Jing; Tong, Chao"

作者地址："[Yuan, Xi; Liu, Xiyao; Zhu, Fangyu; Huang, Biao; Lin, Li; Fu, Yong; Qi, Hongbo; Tong, Chao] Chongqing Med Univ, Affiliated Hosp 1, State Key Lab Maternal & Fetal Med Chongqing Munic, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Yuan, Xi; Liu, Xiyao; Zhu, Fangyu; Huang, Biao; Lin, Li; Fu, Yong; Qi, Hongbo; Tang, Jing; Tong, Chao] Chongqing Med Univ, Chinese Minist Educ, Int Collaborat Lab Reprod & Dev, Chongqing, Peoples R China; [Huang, Jiayu] Chongqing Med Univ, Affiliated Hosp 1, Reprod Med Ctr, Chongqing, Peoples R China; [Kilby, Mark D.] Birmingham Womens & Childrens Fdn Trust, Fetal Med Ctr, Birmingham, England; [Kilby, Mark D.] Univ Birmingham, Coll Med & Dent Sci, Inst Metab & Syst Res, Birmingham, England; [Baker, Philip N.] Univ Leicester, Coll Life Sci, Leicester, England; [Wu, Weiwei] Shanxi Med Univ, Sch Publ Hlth, Dept Epidemiol, Taiyuan, Shanxi, Peoples R China; [Qi, Hongbo] Chongqing Med Univ, Women & Childrens Hosp, Dept Obstet, Chongqing, Peoples R China; [Tang, Jing] Chongqing Med Univ, Sch Basic Med, Chongqing, Peoples R China"

通信作者："Tong, C (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, State Key Lab Maternal & Fetal Med Chongqing Munic, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF HYPERTENSION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001100908200006

JCR分区：Q1

影响因子：4.9

年份：2023

卷号：41

期号：12

开始页：2095

结束页：2106

文献类型：Article

关键词：endoplasmic reticulum stress; placenta; preeclampsia; syncytialization; trophoblast

摘要："Objective:Syncytiotrophoblasts form via mononuclear cytotrophoblast fusion during placentation and play a critical role in maternal-fetal communication. Impaired syncytialization inevitably leads to pregnancy-associated complications, including preeclampsia. Endoplasmic reticulum stress (ERS) is reportedly linked with preeclampsia, but little is known about its association with syncytialization. High temperature requirement factor A4 (HtrA4), a placental-specific protease, is responsible for protein quality control and placental syncytialization. This study aimed to investigate the relationship among HtrA4, ERS, and trophoblast syncytialization in the development of early-onset preeclampsia (EO-PE).Methods:HtrA4 expression and ERS in preeclamptic placentas and control placentas were analyzed by Western blotting and qRT-PCR. HtrA4 and ERS localization in placentas was determined by immunohistochemistry and immunofluorescence. BeWo cells were used to stimulate the effects of HtrA4 and ERS on syncytialization.Results:HtrA4 expression was upregulated in EO-PE and positively correlated with ERS. HtrA4 activity was increased in preeclampsia. Under normoxia, HtrA4 overexpression in BeWo cells did not alter the ERS level. In addition, treatment with hypoxia/reoxygenation (H/R) or an ERS inducer increased HtrA4 expression. HtrA4 upregulation suppressed the levels of syncytin-2 and beta-HCG in the presence of forskolin (FSK), and this change was exaggerated after ERS activation. In addition, treatment with an ERS inhibitor markedly suppressed FSK-treated cell fusion in a manner related to downregulation of HtrA4 expression.Conclusion:Our results suggest that ERS enables syncytialization of placental development by upregulating HtrA4, but that excessive HtrA4 expression and preexisting ERS impair syncytialization and cause EO-PE."

基金机构："National Key R&D Programof China [2022YFC2702400]; National Natural Science Foundation of China [81701479, U21A20346, 82101711, 82171662]; Chongqing Science and Technology Commission [cstc2021ycjh-bgzxm0192, cstc2019jcyj-msxmX0344]; Chongqing Education Commission [KJZD-K202100404]"

基金资助正文："This work was supported by the National Key R & D Programof China (2022YFC2702400), National Natural Science Foundation of China (81701479, U21A20346, 82101711 and 82171662), Chongqing Science and Technology Commission(cstc2021ycjh-bgzxm0192, cstc2019jcyj-msxmX0344) and Chongqing Education Commission (KJZD-K202100404)"