Maintaining the homeostasis of the placental vasculature is of paramount importance for ensuring normal fetal growth and development. Any disruption in this balance can lead to perinatal morbidity. Several studies have uncovered an association between high levels of oxidized cholesterol (oxysterols), and complications during pregnancy, including gestational diabetes mellitus (GDM) and preeclampsia (PE). These complications often coincide with disturbances in placental vascular function. Here, we investigate the role of two oxysterols (7-ketocholesterol, 7β-hydroxycholesterol) in (dys)function of primary fetoplacental endothelial cells (fpEC). Our findings reveal that oxysterols exert a disruptive influence on fpEC function by elevating the production of reactive oxygen species (ROS) and interfering with mitochondrial transmembrane potential, leading to its depolarization. Moreover, oxysterol-treated fpEC exhibited alterations in intracellular calcium (Ca) levels, resulting in the reorganization of cell junctions and a corresponding increase in membrane stiffness and vascular permeability. Additionally, we observed an enhanced adhesion of THP-1 monocytes to fpEC following oxysterol treatment. We explored the influence of activating the Liver X Receptor (LXR) with the synthetic agonist T0901317 (TO) on oxysterol-induced endothelial dysfunction in fpEC. Our results demonstrate that LXR activation effectively reversed oxysterol-induced ROS generation, monocyte adhesion, and cell junction permeability in fpEC. Although the effects on mitochondrial depolarization and calcium mobilization did not reach statistical significance, a strong trend towards stabilization of calcium mobilization was evident in LXR-activated cells. Taken together, our results suggest that high levels of systemic oxysterols link to placental vascular dysfunction and LXR agonists may alleviate their impact on fetoplacental vasculature.

中文翻译：

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肝脏 X 受体激活可减轻氧甾醇诱导的胎儿胎盘内皮细胞功能障碍

维持胎盘脉管系统的稳态对于确保胎儿正常生长和发育至关重要。这种平衡的任何破坏都可能导致围产期发病。多项研究发现，高水平的氧化胆固醇（氧甾醇）与妊娠期并发症（包括妊娠期糖尿病 (GDM) 和先兆子痫 (PE)）之间存在关联。这些并发症通常与胎盘血管功能紊乱同时发生。在这里，我们研究了两种氧甾醇（7-酮胆固醇、7β-羟基胆固醇）在原代胎儿胎盘内皮细胞（fpEC）功能（功能障碍）中的作用。我们的研究结果表明，氧甾醇通过提高活性氧 (ROS) 的产生并干扰线粒体跨膜电位，导致其去极化，对 fpEC 功能产生破坏性影响。此外，经氧甾醇处理的 fpEC 表现出细胞内钙 (Ca) 水平的改变，导致细胞连接的重组以及膜硬度和血管通透性的相应增加。此外，我们观察到氧甾醇处理后 THP-1 单核细胞对 fpEC 的粘附增强。我们探讨了使用合成激动剂 T0901317 (TO) 激活肝脏 X 受体 (LXR) 对氧甾醇诱导的 fpEC 内皮功能障碍的影响。我们的结果表明，LXR 激活有效逆转了 fpEC 中氧甾醇诱导的 ROS 生成、单核细胞粘附和细胞连接通透性。尽管对线粒体去极化和钙动员的影响未达到统计学显着性，但在 LXR 激活的细胞中，钙动员稳定的强烈趋势是明显的。综上所述，我们的结果表明，高水平的全身氧甾醇与胎盘血管功能障碍有关，LXR 激动剂可能减轻它们对胎儿胎盘脉管系统的影响。