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

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 and Tong, Chao (2023) Endoplasmic reticulum stress impairs trophoblast syncytialization through upregulation of HtrA4 and causes early-onset preeclampsia. Journal of Hypertension, 41 (12). pp. 2095-2106. ISSN 0263-6352

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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.

Item Type:	Article
Additional Information:	Funding information: This work was supported by the National Key R&D Program of 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).
Uncontrolled Keywords:	endoplasmic reticulum stress,placenta,preeclampsia,syncytialization,trophoblast,internal medicine,physiology,cardiology and cardiovascular medicine ,/dk/atira/pure/subjectarea/asjc/2700/2724
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	30 May 2025 14:30
Last Modified:	30 May 2025 14:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99358
DOI:	10.1097/HJH.0000000000003541

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