Altered neurovascular coupling and brain arginine metabolism in endothelial nitric oxide synthase deficient mice
Altered neurovascular coupling and brain arginine metabolism in endothelial nitric oxide synthase deficient mice
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DOI：
10.1016/j.niox.2019.03.006
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发表时间：
2019-06-01
影响因子：
3.9
通讯作者：
Liu, Ping
中科院分区：
文献类型：
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作者：
Hariharan, Ashwini;Jing, Yu;Liu, Ping
内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）是脑血流动力学的关键调节因子。具有eNOS缺陷（eNOS（-/-））的小鼠显示出脑中淀粉样蛋白β的年龄相关性增加和记忆缺陷，这暗示了eNOS功能障碍在阿尔茨海默病（AD）的神经发病机制和/或发展中。本研究系统研究了14月龄雄性和雌性野生型（WT）和eNOS（-/-）小鼠的行为、CBF和脑精氨酸代谢谱变化。eNOS（-/-）小鼠在Y-迷宫和旷场试验中表现出行为改变。实时微循环成像仪显示，与性别匹配的WT对照组相比，雄性和雌性eNOS（-/-）小鼠的基础CBF存在显著性别差异，并且对桶状皮质中触须刺激的灌注反应显著增加。7-硝基吲唑治疗阻断eNOS（-/-）小鼠对触须刺激的灌注反应增加。神经化学上，最有趣的变化是在雄性和雌性eNOS（-/-）小鼠的额叶皮质、海马、海马旁区和小脑中谷氨酰胺水平显著降低。这些结果表明，改变的行为功能，神经血管耦合和脑精氨酸代谢（特别是谷氨酰胺）的eNOS缺乏的条件下，进一步支持eNOS功能障碍在AD神经发病机制中的作用。
Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is a key regulator of cerebral blood flow (CBF) dynamics. Mice with eNOS deficiency (eNOS(-/-)) display age-related increases in amyloid beta in the brain and memory deficits, implicating eNOS dysfunction in the neuropathogenesis and/or development of Alzheimer's disease (AD). The present study systematically investigated behavioural, CBF and brain arginine metabolic profile changes in male and female wildtype (WT) and eNOS(-/-) mice at 14 months of age. eNOS(-/-) mice displayed altered behaviour in the Y-maze and open field tests. A real-time microcirculation imager revealed a significant sex difference in the basal CBF and significantly increased perfusion response to whisker stimulations in the Barrel cortex in both male and female eNOS(-/-) mice relative to their sex-matched WT controls. The treatment of 7-nitroindazole blocked the increased perfusion response to whisker stimulations in eNOS(-/-) mice. Neurochemically, the most intriguing changes were markedly reduced glutamine levels in both male and female eNOS(-/-) mice in the frontal cortex, hippocampus, parahippocampal region and cerebellum. These findings demonstrate altered behavioural function, neurovascular coupling and brain arginine metabolism (glutamine in particular) under the condition of eNOS deficiency, which further supports the role of eNOS dysfunction in the AD neuropathogenesis.