Aims Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored. Methods and results We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)−/−) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein–metabolism-associated gene expression in Nfat5-deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)—a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth—in capillary MLEC of hypoxia-exposed Nfat5(EC)−/− mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries. Conclusion Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature.

中文翻译：

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活化 T 细胞的核因子 5 对于肺内皮细胞对缺氧的平衡适应性转录反应是必不可少的


目的 慢性缺氧会导致肺部有害的结构改变，这可能导致肺动脉高压，部分由内皮介导。虽然它与缺氧相关肺部疾病发展的相关性是众所周知的，但控制肺内皮对缺氧的初始适应的决定因素在很大程度上仍未得到探索。方法和结果我们揭示了缺氧激活活化 T 细胞的转录因子核因子 5 （NFAT5），并研究了其在小鼠肺内皮细胞 （MLECs） 中的调节功能。与对照小鼠相比，暴露于常压缺氧 （10% O 2 ） 21 天的小鼠 EC 特异性敲除 Nfat5 （Nfat5（EC） - / - ） 促进血管纤维化并加剧肺右心室收缩压的增加以及右心室功能障碍。基于微阵列和单细胞 RNA 测序的分析显示，暴露于缺氧 7 天后，Nfat5 缺陷型 MLEC 中的生长因子、能量和蛋白质代谢相关基因表达受损。具体来说，NFAT5 的缺失促进了血小板衍生生长因子 B （Pdgfb） 的表达和释放——一种缺氧诱导因子 1 α （HIF1α） 调节的血管平滑肌细胞 （VSMC） 生长的驱动因素——在缺氧暴露的 Nfat5 （EC） −/− 小鼠的毛细血管 MLEC 中，伴随着 VSMC 对远端肺动脉的覆盖增强。结论 总的来说，我们的研究表明，MLEC 对缺氧的早期和短暂亚群特异性反应可能决定后期器官功能障碍的程度。在这种情况下，NFAT5 充当快速调整内皮转录组以应对缺氧所需的保护性转录因子。 具体来说，NFAT5 限制了 HIF1α 介导的 Pdgfb 表达，从而限制了肺血管系统的肌肉化和抵抗。