Intermittent Hypoxia Impairs Trophoblast Cell Viability by Triggering the Endoplasmic Reticulum Stress Pathway
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ORIGINAL ARTICLE
Intermittent Hypoxia Impairs Trophoblast Cell Viability by Triggering the Endoplasmic Reticulum Stress Pathway Wei Song 1 & Wen-Lin Chang 2,3 & Dan Shan 1 & Yanli Gu 4 & Lei Gao 1 & Shengnan Liang 1 & Huan Guo 5 & Jing Yu 6 & Xiaowei Liu 1 Received: 28 November 2018 / Accepted: 31 July 2019 # Society for Reproductive Investigation 2020
Abstract Intermittent hypoxia (IH) is a prominent characteristic of many clinical complications such as obstructive sleep apnea syndrome (OSAS). OSAS is related to a higher incidence of adverse pregnancy outcomes, and IH has been suggested as the preliminary physiological etiology. However, further studies remain to be performed on the underlying cellular and molecular pathogenic mechanisms of OSAS-related IH on adverse pregnancy outcomes. Here, we used a trophoblast cell line (HTR8/SVneo), primary extravillous trophoblast cells (EVTs), and a normal-term placenta villi explant culture model in vitro in this research. The effects and possible molecular mechanisms of IH on trophoblast motility, cell cycle progression, and apoptosis were investigated. IH reduced HTR8/SVneo cell and EVT motility significantly, which could be partially attributed to the reduced secretion of matrix metalloproteinase 2. IH treatment blocked HTR8/SVneo cell proliferation significantly by modulating the expression of D-type Cyclins. IH also induced significant trophoblast cell apoptosis. Moreover, our study supports the premise that IH attenuates trophoblast cell motility and proliferation and induces excessive trophoblast cell apoptosis by specifically triggering the endoplasmic reticulum (ER) stress signaling pathway. Briefly, differing from the mechanism of trophoblast motility and proliferation inhibition, and apoptosis induction by hypoxia, IH is apt to weaken trophoblast viability mainly by activating the ER stress signaling pathway with a time-dependent pattern, which is further implicated in OSAS-associated adverse pregnancy outcomes. Keywords Intermittent hypoxia . Endoplasmic reticulum stress . Trophoblast invasion and migration . Cell cycle arrest . Apoptosis
Introduction Oxidative stress, a subsequent outcome of hypoxia– reoxygenation or chronic intermittent hypoxia (IH) exposure, is a prominent placental feature in many complications of pregnancy [1]. IH is the hallmark feature of obstructive sleep
apnea syndrome (OSAS), which is characterized by chronic, repetitive short cycles of oxygen desaturation and then rapid reoxygenation [2], and is estimated to affect 5–6% of the general population [3, 4]. OSAS is associated with hypertension, cardiovascular disease, chronic fatigue syndrome, and fibromyalgia in general adult populations [5, 6].
Wei Song and Wen-Lin Chang contributed equally to this work. * Jing Yu [email protected] * Xiaowei Liu [email protected] 1
2
Department of Beijing Obstetric and Gyneocology Hospital, Capital Medical University, Beijing 100026, China Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology,
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