Division of Neurosurgery, St Michael's Hospital, Keenan Research Centre in Li Ka Shing Knowledge Institute of St Michael's Hospital and Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
J Cereb Blood Flow Metab. 2011 Jan;31(1):190-9. doi: 10.1038/jcbfm.2010.76. Epub 2010 Jun 2.
We studied whether endothelial nitric oxide synthase (eNOS) is upregulated and uncoupled in large cerebral arteries after subarachnoid hemorrhage (SAH) and also whether this causes cerebral vasospasm in a mouse model of anterior circulation SAH. Control animals underwent injection of saline instead of blood (n=16 SAH and n=16 controls). There was significant vasospasm of the middle cerebral artery 2 days after SAH (lumen radius/wall thickness ratio 4.3 ± 1.3 for SAH, 23.2 ± 2.1 for saline, P<0.001). Subarachnoid hemorrhage was associated with terminal deoxynucleotidyl transferase dUTP nick-end labeling, cleaved caspase-3, and Fluoro-Jade-positive neurons in the cortex and with CA1 and dentate regions in the hippocampus. There were multiple fibrinogen-positive microthromboemboli in the cortex and hippocampus after SAH. Transgenic mice expressing lacZ under control of the eNOS promoter had increased X-gal staining in large arteries after SAH, and this was confirmed by the increased eNOS protein on western blotting. Evidence that eNOS was uncoupled was found in that nitric oxide availability was decreased, and superoxide and peroxynitrite concentrations were increased in the brains of mice with SAH. This study suggests that artery constriction by SAH upregulates eNOS but that it is uncoupled and produces peroxynitrite that may generate microemboli that travel distally and contribute to brain injury.
我们研究了蛛网膜下腔出血（SAH）后大脑血管内皮型一氧化氮合酶（eNOS）是否上调和脱耦联，以及这种情况是否会在小鼠前循环 SAH 模型中引起脑血管痉挛。对照组动物接受盐水而不是血液注射（SAH n=16，对照组 n=16）。SAH 后 2 天大脑中动脉明显痉挛（管腔半径/壁厚度比 SAH 为 4.3±1.3，盐水为 23.2±2.1，P<0.001）。蛛网膜下腔出血与皮质中的末端脱氧核苷酸转移酶 dUTP 缺口末端标记、裂解 caspase-3 和 Fluoro-Jade 阳性神经元以及海马体中的 CA1 和齿状回有关。SAH 后皮质和海马体有多个纤维蛋白原阳性微血栓。在 eNOS 启动子控制下表达 lacZ 的转基因小鼠在 SAH 后大动脉中 X-gal 染色增加，这在western blot 上增加的 eNOS 蛋白中得到证实。发现 eNOS 脱偶联的证据是，一氧化氮的可用性降低，并且 SAH 小鼠大脑中的超氧化物和过氧亚硝酸盐浓度增加。这项研究表明，SAH 引起的动脉收缩会上调 eNOS，但它是脱偶联的，并产生可能产生微栓子的过氧亚硝酸盐，这些微栓子会向远处移动并导致脑损伤。
