Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g. eicosapentanoic acid, docosahexaenoic acid, alpha-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxydocosapentaenoic acid), and higher levels of some omega-6 metabolites (p<0.02) including 15-Keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

中文翻译：

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妊娠长期缺氧诱导胎羊肺动脉代谢组学重编程和表型转变

妊娠期长期缺氧会增加婴儿患多种疾病的风险，包括持续性肺动脉高压。与人类相似，胎羊肺发育容易受到长期宫内缺氧的影响，其结构和功能变化与肺动脉高压的发展相关，包括肺动脉内壁增厚和动脉反应性失调，最终导致右心室输出量减少。为了进一步探索与胎羊肺缺氧引起的畸变相关的机制，我们检查了由于宫内长期缺氧而发生代谢组学变化和功能表型转变的前提。为了解决这个问题，我们进行了电子显微镜、蛋白质免疫印迹、钙成像、对在妊娠后期 110 天以上暴露于低海拔或高海拔 (3801 m) 缺氧环境的近期胎羊中分离的肺动脉进行代谢组学分析。我们的结果表明，在缺氧组中，肌浆网肿胀，管腔宽度大，与质膜的距离较远。缺氧动物表现出较高的内质网应激和抑制钙储存。在代谢方面，缺氧与多种 omega-3 多不饱和脂肪酸和衍生脂质介质（例如二十碳五烯酸、二十二碳六烯酸、α-亚麻酸、5-羟基二十碳五烯酸 (5-HEPE)、12-HEPE、15-HEPE）水平较低有关、前列腺素 E3 和 19(20)-环氧二十二碳五烯酸），以及更高水平的一些 omega-6 代谢物（p<0. 02) 包括 15-Keto 前列腺素 E2 和亚油酰甘油。总的来说，这些结果揭示了长期缺氧诱导的胎羊肺动脉代谢重编程和表型转变的广泛证据，这些条件可能导致持续性肺动脉高压的发展。