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.
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