Perinatal hypoxia induces permanent structural and functional changes in the lung and its pulmonary circulation that are associated with the development of pulmonary hypertension (PH) in later life. The mechanistic target of the rapamycin (mTOR) pathway is vital for fetal lung development and implicated in hypoxia-associated PH, yet its involvement in the developmental programming of PH remains unclear. Pregnant C57/BL6 dams were placed in hyperbaric (760 mmHg) or hypobaric chambers during gestation (505 mmHg, day 15 through postnatal day 4) or adulthood (420 mmHg, postnatal day 21 through 8wks). Pulmonary hemodynamics and right ventricular systolic pressure (RVSP) were measured at 8wks. mTOR pathway proteins were assessed in fetal (day 18.5) and adult lung (8wks). Perinatal hypoxia induced PH during adulthood, even in the absence of a sustained secondary hypoxic exposure, as indicated by reduced pulmonary artery acceleration time (PAAT) and peak flow velocity through the pulmonary valve, as well as greater RVSP, RV wall thickness and RV/LV weight. Such effects were independent of increased blood viscosity. In fetal lung homogenates, hypoxia reduced the expression of critical downstream mTOR targets, most prominently total and phosphorylated 4EBP1, as well as vascular endothelial growth factor, a central regulator of angiogenesis in the fetal lung. In contrast, adult offspring of hypoxic dams tended to have elevated p4EBP1 compared to controls. Our data suggest that inhibition of mTORC1 activity in the fetal lung as a result of gestational hypoxia may interrupt pulmonary vascular development and thereby contribute to the developmental programming of PH.

中文翻译：

---

低氧诱导的肺发育过程中 mTORC1 活性的抑制：肺动脉高压发育程序化的可能机制

围产期缺氧会引起肺及其肺循环的永久性结构和功能变化，这些变化与晚年肺动脉高压 (PH) 的发展有关。雷帕霉素 (mTOR) 通路的机制靶点对胎儿肺发育至关重要，并与缺氧相关的 PH 相关，但其参与 PH 的发育程序仍不清楚。在妊娠期（505 mmHg，第 15 天至出生后第 4 天）或成年期（420 mmHg，出生后第 21 天至 8 周）将怀孕的 C57/BL6 水坝置于高压（760 mmHg）或低压舱中。在 8 周时测量肺血流动力学和右心室收缩压 (RVSP)。在胎儿（第 18.5 天）和成人肺（8 周）中评估 mTOR 通路蛋白。成年期围产期缺氧诱发 PH，即使在没有持续的继发性低氧暴露的情况下，肺动脉加速时间 (PAAT) 和通过肺动脉瓣的峰值流速以及更大的 RVSP、RV 壁厚度和 RV/LV 重量都表明了这一点。这种影响与增加的血液粘度无关。在胎儿肺匀浆中，缺氧降低了关键下游 mTOR 靶标的表达，最显着的是总和磷酸化 4EBP1，以及血管内皮生长因子，胎儿肺中血管生成的中心调节因子。相比之下，与对照组相比，缺氧水坝的成年后代往往具有升高的 p4EBP1。我们的数据表明，由于妊娠缺氧而抑制胎儿肺中的 mTORC1 活性可能会中断肺血管发育，从而有助于 PH 的发育程序化。