Institute for Fetology, First Hospital of Soochow University, Suzhou, China; Wuxi Maternal & Child Health Hospital, Jiangsu, China.
Institute for Fetology, First Hospital of Soochow University, Suzhou, China.
Reprod Toxicol. 2021 Oct;105:91-100. doi: 10.1016/j.reprotox.2021.08.009. Epub 2021 Aug 31.
Pulmonary arterial hypertension is a progressive disorder characterized by remodeling and increased small pulmonary arteries resistance. Endothelin-1 (ET-1) was related to PAH and ET-1 receptors were up-regulated selectively in the lung when exposed to toxic factor hypoxia. However, the role of ET-1 signaling in the pathogenesis of prenatal hypoxia-induced pulmonary abnormalities remains to be elucidated. Pregnant rats were divided into prenatal hypoxia (10.5 % O from gestational day 4-21) and control group. Their three-month-old offspring male rats were tested for vascular functions and molecular analysis, DNA methylation was assessed for cellular hypoxia. Functional testing showed that ET-1-mediated vasoconstriction was enhanced, and the expressions of endothelin A receptor/B receptor (ETR/ETR), inositol 1,4,5-trisphosphate receptor, type 1, and the sensitivity of calcium channels were increased in the small pulmonary arteries following prenatal hypoxia. q-PCR and DHE staining showed that the expressions of NADPH oxidase 1/4 (Nox1/4) were up-regulated, along with the increased production of superoxide anion. Furthermore, superoxide anion promoted ET-1-mediated pulmonary artery contraction. In the pulmonary artery smooth muscle cell experiments, q-PCR, Western Blot, CCK8 and DHE staining showed that the expressions of ETR, Nox1/4, and superoxide anion were increased by hypoxia, along with promoted cell proliferation. 2,2,6,6-Tetramethyl-1-piperidinyloxy reversed hypoxia-induced cell proliferation. ETR antagonist BQ788 inhibited hypoxia-increased expressions of Nox1/4, superoxide anion production, and proliferation of cells. Moreover, methylation analysis indicated that hypoxia decreased the methylation levels of the ETR promoter in the pulmonary artery smooth muscle cells. The results indicated that prenatal toxic factor hypoxia resulted in abnormal ETR activation, which enhanced ET-1-mediated vasoconstriction of pulmonary arteries and pulmonary artery smooth muscle cell proliferation through ETR/Nox1/4-derived ROS pathway.
肺动脉高压是一种进行性疾病，其特征为重塑和增加小肺动脉阻力。内皮素-1（ET-1）与 PAH 有关，当暴露于有毒缺氧因素时，ET-1 受体在肺中选择性地上调。然而，ET-1 信号在产前缺氧引起的肺异常发病机制中的作用仍有待阐明。将怀孕大鼠分为产前缺氧（从妊娠第 4-21 天 10.5%O 2）和对照组。对其 3 个月大的雄性后代大鼠进行血管功能和分子分析测试，评估细胞缺氧的 DNA 甲基化。功能测试表明，产前缺氧后小肺动脉中 ET-1 介导的血管收缩增强，内皮素 A 受体/受体（ETR/ETR）、肌醇 1,4,5-三磷酸受体 1 型和钙通道的敏感性表达增加。q-PCR 和 DHE 染色显示 NADPH 氧化酶 1/4（Nox1/4）的表达上调，同时超氧阴离子的产生增加。此外，超氧阴离子促进 ET-1 介导的肺动脉收缩。在肺动脉平滑肌细胞实验中，q-PCR、Western Blot、CCK8 和 DHE 染色显示，缺氧增加了 ETR、Nox1/4 和超氧阴离子的表达，同时促进了细胞增殖。2,2,6,6-四甲基-1-哌啶醇氧化物逆转了缺氧诱导的细胞增殖。ETR 拮抗剂 BQ788 抑制了缺氧增加的 Nox1/4 表达、超氧阴离子产生和细胞增殖。此外，甲基化分析表明，缺氧降低了肺动脉平滑肌细胞中 ETR 启动子的甲基化水平。结果表明，产前有毒因素缺氧导致异常的 ETR 激活，通过 ETR/Nox1/4 衍生的 ROS 途径增强 ET-1 介导的肺动脉收缩和肺动脉平滑肌细胞增殖。
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