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<p>Early-onset preeclampsia remains a significant cause of maternal and neonatal morbidity; however, its multifactorial etiology is not yet fully elucidated. This narrative review aims to synthesize current evidence on the progression from placental ischemia to cellular stress, with a specific focus on how the unfolded protein response (UPR) drives the pathogenesis of early-onset preeclampsia. For a thematic synthesis of the literature, data from human clinical samples, animal models, and cell cultures were integrated to construct a comprehensive mechanistic model. At its core, a critical "vicious cycle" exists where defective spiral artery remodeling and reduced NO bioavailability trigger persistent hypoxia. This hypoxic environment disrupts endoplasmic reticulum (ER) calcium homeostasis by impairing ATP-dependent SERCA activity, subsequently activating the UPR. The synergistic interaction between reactive oxygen species (ROS) accumulation and ER stress serves as the primary driver for trophoblast apoptosis and the systemic release of anti-angiogenic factors (sFlt-1, sEng), ultimately resulting in maternal endothelial dysfunction. ER stress pathways represent viable therapeutic targets. In experimental models, chemical chaperones such as 4-PBA and TUDCA have been shown to mitigate ER stress-induced placental damage and improve angiogenic balance. However, clinical translation requires longitudinal cohort studies to validate UPR biomarkers (GRP78/XBP1) across different trimesters.</p>

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The Pathogenesis of Preeclampsia: Hypoxia and the Unfolded Protein Response

  • 期刊论文

  • 发表日期：

    2026年7月1日

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  • Nesibe Yildiz,
  • Hakan Ekmekci

摘要

Early-onset preeclampsia remains a significant cause of maternal and neonatal morbidity; however, its multifactorial etiology is not yet fully elucidated. This narrative review aims to synthesize current evidence on the progression from placental ischemia to cellular stress, with a specific focus on how the unfolded protein response (UPR) drives the pathogenesis of early-onset preeclampsia. For a thematic synthesis of the literature, data from human clinical samples, animal models, and cell cultures were integrated to construct a comprehensive mechanistic model. At its core, a critical "vicious cycle" exists where defective spiral artery remodeling and reduced NO bioavailability trigger persistent hypoxia. This hypoxic environment disrupts endoplasmic reticulum (ER) calcium homeostasis by impairing ATP-dependent SERCA activity, subsequently activating the UPR. The synergistic interaction between reactive oxygen species (ROS) accumulation and ER stress serves as the primary driver for trophoblast apoptosis and the systemic release of anti-angiogenic factors (sFlt-1, sEng), ultimately resulting in maternal endothelial dysfunction. ER stress pathways represent viable therapeutic targets. In experimental models, chemical chaperones such as 4-PBA and TUDCA have been shown to mitigate ER stress-induced placental damage and improve angiogenic balance. However, clinical translation requires longitudinal cohort studies to validate UPR biomarkers (GRP78/XBP1) across different trimesters.