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, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China.
Reprod Sci. 2020 Feb;27(2):477-487. doi: 10.1007/s43032-019-00039-y. Epub 2020 Feb 3.
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.
间歇性低氧（IH）是许多临床并发症的突出特征，如阻塞性睡眠呼吸暂停综合征（OSAS）。OSAS 与不良妊娠结局的发生率较高有关，而 IH 被认为是初步的生理病因。然而，关于 OSAS 相关 IH 对不良妊娠结局的潜在细胞和分子发病机制仍需要进一步研究。在这里，我们在这项研究中使用了滋养层细胞系（HTR8/SVneo）、原代绒毛外滋养层细胞（EVT）和正常足月胎盘绒毛外植体培养模型。研究了 IH 对滋养层运动、细胞周期进程和细胞凋亡的影响及其可能的分子机制。IH 显著降低了 HTR8/SVneo 细胞和 EVT 的运动能力，这可能部分归因于基质金属蛋白酶 2 的分泌减少。IH 通过调节 D 型细胞周期蛋白的表达显著抑制了 HTR8/SVneo 细胞的增殖。IH 还诱导了显著的滋养层细胞凋亡。此外，我们的研究支持这样一个前提，即 IH 通过特异性触发内质网（ER）应激信号通路，减弱滋养层细胞的运动和增殖能力，并诱导过度的滋养层细胞凋亡。简而言之，与缺氧抑制滋养层运动和增殖以及诱导细胞凋亡的机制不同，IH 主要通过激活 ER 应激信号通路，以时间依赖性方式减弱滋养层细胞活力，这与 OSAS 相关的不良妊娠结局有关。
