Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm.
Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm.
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DOI：
10.1161/strokeaha.110.607200
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发表时间：
2011-03
期刊：
影响因子：
8.3
通讯作者：
Zipfel GJ
中科院分区：
文献类型：
--
作者：
Vellimana AK;Milner E;Azad TD;Harries MD;Zhou ML;Gidday JM;Han BH;Zipfel GJ
血管痉挛引起的迟发性脑缺血（DCI）仍然是动脉瘤性蛛网膜下腔出血（SAH）患者发病的主要来源。我们假设通过预处理（PC）激活先天神经血管保护机制可能代表一种针对SAH引起的血管痉挛和神经功能缺损的新治疗方法；其次，它提供的神经血管保护是由内皮一氧化氮合酶（eNOS）介导的。野生型 (WT) 小鼠接受低氧 PC 或常氧治疗，24 小时后接受 SAH。每天分析神经功能；术后第 2 天评估血管痉挛。还评估了 NO 可用性、eNOS 表达和 eNOS 活性。在一项单独的实验中，WT 和 eNOS 缺失小鼠接受低氧 PC 或常氧治疗，随后进行 SAH，并评估血管痉挛和神经功能缺损。 PC 几乎完全预防 SAH 引起的血管痉挛和神经功能缺损。它还可以防止 SAH 引起的 NO 可用性减少，并增加患有和不患有 SAH 的小鼠的 eNOS 活性。在用 NOS 抑制剂 L-NAME 治疗的 WT 小鼠和 eNOS 缺失小鼠中，PC 诱导的针对血管痉挛和神经功能缺损的保护作用消失了。针对血管痉挛的内源性保护机制是存在的，而且是强大的，并且可以通过 PC 诱导。 eNOS 衍生的 NO 是 PC 诱导的神经血管保护的关键介质。这些数据提供了强有力的“原理验证”证据，表明 PC 代表了一种有前途的新策略，可减少 SAH 后的血管痉挛和 DCI。
Vasospasm-induced delayed cerebral ischemia (DCI) remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits; and secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS). Wild type (WT) mice were subjected to hypoxic PC or normoxia followed 24 h later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery day 2. NO availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, WT and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits. PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in NO availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in WT mice treated with the NOS inhibitor L-NAME and in eNOS-null mice. Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced via PC. eNOS-derived NO is a critical mediator of PC-induced neurovascular protection. These data provide strong “proof-of-principle” evidence that PC represents a promising new strategy to reduce vasospasm and DCI after SAH.