Neurovascular Dysfunction, BBB Disruption and Oxidative Stress in Ischemic Brain

脑缺血再灌注时产生的氧化应激是导致脑出血的关键事件 屏障(BBB)破坏，继发血管源性水肿和梗死灶出血性转化 脑组织，限制了溶栓剂对组织再通的益处。我们已经证明了 锰超氧化物歧化酶(SOD2-/)缺乏小鼠的轻度脑缺血(30分钟) 导致与基质金属蛋白酶(MMP)激活相关的延迟(24小时)BBB分解， 发炎和高脑出血率。我们的初步研究进一步表明， 血管内皮细胞NADPH氧化酶的过度表达与出血性疾病的形成 SOD2-/小鼠转化和脑出血及NADPH的抑制作用 氧化物酶显著减少脑出血和脑梗塞体积。我们现在假设内皮细胞的激活 NADPH氧化酶和细胞外信号调节激酶(ERK)1/2表达的信号转导机制 神经血管功能障碍，血脑屏障破坏，以及通过激活基质金属蛋白酶-9导致的内皮细胞死亡。我们的目标是 使用这一新开发的具有延迟血脑屏障中断的SOD2-/小鼠模型来验证这一假设。我们 我相信这些是新的研究，将为最大限度地减少氧化作用的治疗机会提供见解 急性缺血性卒中患者的应激相关出血性转化。

Oxidative stress generated during cerebral ischemia and reperfusion is a critical event leading to bloodbrain barrier (BBB) disruption, with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of tissue reperfusion with thrombolytic agents. We have demonstrated that mild cerebral ischemia (30 minutes) in mice deficient in manganese-superoxide dismutase (SOD2-/+) caused delayed (>24 hours) BBB breakdown associated with activation of matrix metalloproteinase (MMP), inflammation, and high brain hemorrhage rates. Our preliminary studies have further shown that overexpression of endothelial NADPH oxidase is associated with the formation of hemorrhagic transformation and intracerebral hemorrhage (ICH) in the SOD2 -/+ mice, and that inhibition of NADPH oxidase significantly reduces ICH and infarct volume. We now hypothesize that activation of endothelial NADPH oxidase and expression of extracellular signal-regulated kinase (ERK) 1/2 signaling cause neurovascular dysfunction, BBB disruption, and endothelial cell death by activation of MMP-9. Our aim is to test this hypothesis using this newly developed model of SOD2-/+ mice with delayed BBB disruption. We believe these are novel studies that will provide insights into therapeutic opportunities to minimize oxidative stress-associated hemorrhagic transformation in patients who suffer acute ischemic stroke.