Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
PLoS One. 2011;6(6):e21638. doi: 10.1371/journal.pone.0021638. Epub 2011 Jun 27.
The central nervous system normally functions at O(2) levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O(2)-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O(2) tensions compared to the cell culture standard of 20% O(2), to investigate their ability to sense and translate this O(2) information to transcriptional activity. Variance of ambient O(2) tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O(2) tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O(2) tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O(2) tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional 'programs' may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity.
中枢神经系统通常在 O(2) 水平下运作，而大多数其他组织会将其视为缺氧。然而，大多数神经元和星形胶质细胞的体外研究都是在高氧条件下进行的，没有考虑到 O(2)依赖性细胞适应。我们分析了星形胶质细胞对 1%、4%和 9%O(2)张力与细胞培养标准 20%O(2)的反应性，以研究它们感知和将这种 O(2)信息转化为转录活性的能力。大鼠星形胶质细胞周围环境 O(2)张力的变化导致核糖体活性、细胞骨架和能量调节机制以及细胞因子相关信号的深刻变化。转录调节模式的聚类揭示了四个不同的反应模式组，它们围绕 4%O(2)张力定向旋转，或者在不同的氧张力下表现出一致的上升/下降基因表达模式。随着缺氧程度的增加，免疫反应和细胞周期/癌症相关信号通路转录组亚群显著激活，而止血和心血管信号机制则随着缺氧程度的增加而减弱。我们的数据表明，不同的 O(2)张力会诱导特定的、与生理相关的转录调节模式，这些模式可能是连接更高的神经活动与星形胶质细胞功能和周围氧气环境的重要生理机制的基础。这些强烈定义的模式表明，生理转录程序具有强烈的偏向性，围绕着 4%O(2)张力旋转，而不具有这种偏向性的单一模式则更与病理作用有关。这些转录“程序”的功能相互作用可能有助于调节中枢神经系统在应激或活动增加期间的动态血管反应性。
