Carbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation
Carbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation
复制标题
DOI：
10.1161/01.res.0000196681.34485.ec
复制
发表时间：
2005-12-09
影响因子：
20.1
通讯作者：
Suematsu, M
中科院分区：
文献类型：
--
作者：
Ishikawa, M;Kajimura, M;Suematsu, M
尽管大脑会产生一氧化氮和一氧化碳（CO），但这些气体及其酶系统如何相互作用来调节脑血管功能尚不清楚。我们检查了血红素加氧酶 (HO) 产生的 CO 是否调节大鼠软脑膜微循环中组成型 NO 的产生和作用。免疫组织化学分析表明，HO-2 出现在神经元和蛛网膜小梁细胞中，其中可检测到 NO 合酶 1 (NOS1)，并且也出现在表达 NOS3 的血管内皮细胞中，表明 CO 和 NO 生成位点共定位。使用封闭颅窗制备的活体显微镜显示，锌原卟啉 IX 对 H2O2 活性的阻断显着扩张了小动脉。这种血管舒张作用取决于局部 NOS 活性，并可通过补充 CO 消除，这表明源自 HO-2 的气体可强效调节 NO 介导的血管舒张反应。通过二氨基荧光素激光共聚焦显微荧光成像对 NO 进行生物成像，结果表明在微血管壁、硬膜下间皮细胞和蛛网膜小梁细胞中可检测到一定量的 NO，这些细胞在软脑膜微血管系统中和周围表达 NOS。当 H2O 抑制剂抑制 CO 时，这些细胞中局部 NO 的形成增加。这种加速 NO 形成的模式取决于 NOS 活性，并再次因局部 CO 补充而减弱。使用培养的猪主动脉内皮细胞进行的研究表明，CO 对 NOS 的抑制作用可能是由于光可逆气体与假体血红素的结合所致。总的来说，源自 HO-2 的 CO 似乎可以作为强直性血管调节剂，拮抗大鼠脑微循环中 NO 介导的血管舒张。
Although the brain generates NO and carbon monoxide ( CO), it is unknown how these gases and their enzyme systems interact with each other to regulate cerebrovascular function. We examined whether CO produced by heme oxygenase (HO) modulates generation and action of constitutive NO in the rat pial microcirculation. Immunohistochemical analyses indicated that HO-2 occurred in neurons and arachnoid trabecular cells, where NO synthase 1 (NOS1) was detectable, and also in vascular endothelium-expressing NOS3, suggesting colocalization of CO- and NO-generating sites. Intravital microscopy using a closed cranial window preparation revealed that blockade of the HO activity by zinc protoporphyrin IX significantly dilates arterioles. This vasodilatation depended on local NOS activities and was abolished by CO supplementation, suggesting that the gas derived from HO-2 tonically regulates NO-mediated vasodilatory response. Bioimaging of NO by laser-confocal microfluorography of diaminofluorescein indicated detectable amounts of NO at the microvascular wall, the subdural mesothelial cells, and arachnoid trabecular cells, which express NOS in and around the pial microvasculature. On CO inhibition by the HO inhibitor, regional NO formation was augmented in these cells. Such a pattern of accelerated NO formation depended on NOS activities and was again attenuated by the local CO supplementation. Studies using cultured porcine aortic endothelial cells suggested that the inhibitory action of CO on NOS could result from the photo-reversible gas binding to the prosthetic heme. Collectively, CO derived from HO-2 appears to serve as a tonic vasoregulator antagonizing NO-mediated vasodilatation in the rat cerebral microcirculation.