학술논문
Endoplasmic reticulum stress impairs trophoblast syncytialization through upregulation of HtrA4 and causes early-onset preeclampsia.
Document Type
Academic Journal
Author
Yuan X; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Liu X; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Zhu F; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Huang B; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Lin L; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Huang J; Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.; Wen L; Kilby MD; Fetal Medicine Centre, Birmingham Women's & Children's Foundation Trust.; Institute of Metabolism & Systems Research, College of Medical & Dental Sciences, University of Birmingham, Birmingham.; Baker PN; College of Life Sciences, University of Leicester, Leicester, UK.; Fu Y; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Wu W; Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi.; Qi H; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University.; Tang J; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.; School of Basic Medicine, Chongqing Medical University, Chongqing, China.; Tong C; State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University.; International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University.
Source
Publisher: Wolters Kluwer Health, Inc Country of Publication: Netherlands NLM ID: 8306882 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1473-5598 (Electronic) Linking ISSN: 02636352 NLM ISO Abbreviation: J Hypertens Subsets: MEDLINE
Subject
Language
English
Abstract
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 β-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.
(Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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 β-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.
(Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)