Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway
Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway
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DOI：
10.1073/pnas.1119658109
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发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Suematsu, Makoto
中科院分区：
文献类型：
--
作者：
Morikawa, Takayuki;Kajimura, Mayumi;Suematsu, Makoto
缺氧导致的脑血流量增强对于大脑功能至关重要，但其调节背后的信号系统尚不清楚。我们在使用双光子活体激光扫描显微镜监测小脑切片和完整小鼠大脑中血管分布的研究中报告了介导缺氧诱导的脑血管舒张的途径。在这个级联反应中，缺氧通过胱硫醚β-合酶（CBS）形成的H2S和血红素加氧酶（HO）-2产生的CO的协同作用引起脑血管舒张。缺氧会减少氧传感器 HO-2 产生的 CO。组成型 CO 会在生理上抑制 CBS，缺氧会导致 H2S 水平升高，从而介导毛细血管前小动脉的血管舒张。靶向删除 HO-2 或 CBS 的小鼠显示血管对缺氧的反应受损。因此，在 HO-2 缺失小鼠的完整成年大脑大脑皮层中，成像质谱分析显示缺氧时维持 ATP 水平的能力受损。
Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H2S formed by cystathionine beta-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H2S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.