State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Department of Obstetrics, Peking University Third Hospital, Beijing 100191, China.
Oxid Med Cell Longev. 2022 Jun 1;2022:4290922. doi: 10.1155/2022/4290922. eCollection 2022.
Preeclampsia (PE) is associated with insufficient placental perfusion attributed to maldevelopment of the placental vasculature. Reactive oxygen species (ROS) are implicated in angiogenesis, but their regulatory effects and mechanisms in placental vascular development remain unclear.
Placental oxidative stress was determined throughout gestation by measuring 4-hydroxynonenal (4HNE) and malondialdehyde (MDA). The antioxidant MitoQ was administered to pregnant mice from GDs 7.5 to 11.5; placental morphology and angiogenesis pathways were examined on GDs 11.5 and 18.5. Moreover, we established a mouse mFlt-1-induced PE model and assessed blood pressure, urine protein levels, and placental vascular development on GDs 11.5 and 18.5. Human umbilical vein endothelial cells (HUVECs) were treated with various HO concentrations to evaluate cell viability, intracellular ROS levels, and tube formation capability. MitoQ, an AKT inhibitor and an ERK1/2 inhibitor were applied to validate the ROS-mediated mechanism regulating placental angiogenesis.
First-trimester placentas presented significantly higher MDA and 4HNE levels. MitoQ significantly reduced the blood vessel density and angiogenesis pathway activity in the placenta on GDs 11.5 and 18.5. Serum sFlt-1 levels were elevated, and we observed poor placental angiogenesis and PE-like symptoms in cases with mFlt-1 overexpression. Moderate HO treatment promoted HUVEC proliferation and angiogenesis, whereas these improvements were abolished by MitoQ, AKT inhibitor, or ERK1/2 inhibitor treatment.
Moderate ROS levels are essential for placental angiogenesis; diminishing ROS with potent antioxidants during placentation decreases placental angiogenesis and increases PE risk. Therefore, antioxidant therapy should be considered carefully for normal pregnant women during early gestation.
子痫前期（PE）与胎盘血管发育不良导致的胎盘灌注不足有关。活性氧（ROS）参与血管生成，但它们在胎盘血管发育中的调节作用和机制尚不清楚。
通过测量 4-羟基壬烯醛（4HNE）和丙二醛（MDA），在整个孕期确定胎盘的氧化应激。从妊娠第 7.5 天到第 11.5 天，给怀孕的老鼠施用抗氧化剂 MitoQ；在妊娠第 11.5 天和第 18.5 天检查胎盘形态和血管生成途径。此外，我们建立了一个小鼠 mFlt-1 诱导的 PE 模型，并在妊娠第 11.5 天和第 18.5 天评估血压、尿蛋白水平和胎盘血管发育。用不同的 HO 浓度处理人脐静脉内皮细胞（HUVEC），以评估细胞活力、细胞内 ROS 水平和管形成能力。用 MitoQ、AKT 抑制剂和 ERK1/2 抑制剂处理，验证调节胎盘血管生成的 ROS 介导的机制。
在妊娠早期，胎盘的 MDA 和 4HNE 水平明显升高。MitoQ 在妊娠第 11.5 天和第 18.5 天显著降低了胎盘的血管密度和血管生成途径活性。血清 sFlt-1 水平升高，我们观察到 mFlt-1 过表达时胎盘血管生成不良和 PE 样症状。中等 HO 处理促进 HUVEC 增殖和血管生成，而 MitoQ、AKT 抑制剂或 ERK1/2 抑制剂处理则消除了这些改善。
适度的 ROS 水平对胎盘血管生成至关重要；在胎盘形成期间，用强效抗氧化剂减少 ROS 会降低胎盘血管生成并增加 PE 风险。因此，在孕早期，应谨慎考虑对正常孕妇进行抗氧化治疗。
