O'Brien Katie A, Murray Andrew J, Simonson Tatum S
Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Life (Basel). 2022 Mar 16;12(3):437. doi: 10.3390/life12030437.
Hypoxia triggers complex inter- and intracellular signals that regulate tissue oxygen (O) homeostasis, adjusting convective O delivery and utilization (i.e., metabolism). Human populations have been exposed to high-altitude hypoxia for thousands of years and, in doing so, have undergone natural selection of multiple gene regions supporting adaptive traits. Some of the strongest selection signals identified in highland populations emanate from hypoxia-inducible factor (HIF) pathway genes. The HIF pathway is a master regulator of the cellular hypoxic response, but it is not the only regulatory pathway under positive selection. For instance, regions linked to the highly conserved Notch signaling pathway are also top targets, and this pathway is likely to play essential roles that confer hypoxia tolerance. Here, we explored the importance of the Notch pathway in mediating the cellular hypoxic response. We assessed transcriptional regulation of the Notch pathway, including close cross-talk with HIF signaling, and its involvement in the mediation of angiogenesis, cellular metabolism, inflammation, and oxidative stress, relating these functions to generational hypoxia adaptation.
缺氧会触发复杂的细胞间和细胞内信号，这些信号调节组织氧（O）稳态，调节对流性氧输送和利用（即代谢）。人类群体已经暴露于高海拔缺氧环境数千年，在此过程中，多个支持适应性特征的基因区域经历了自然选择。在高原人群中发现的一些最强选择信号来自缺氧诱导因子（HIF）通路基因。HIF通路是细胞缺氧反应的主要调节因子，但它不是唯一处于正选择下的调节通路。例如，与高度保守的Notch信号通路相关的区域也是主要靶点，并且该通路可能在赋予缺氧耐受性方面发挥重要作用。在这里，我们探讨了Notch通路在介导细胞缺氧反应中的重要性。我们评估了Notch通路的转录调控，包括与HIF信号的密切相互作用，以及它在血管生成、细胞代谢、炎症和氧化应激介导中的作用，并将这些功能与世代性缺氧适应联系起来。
