Neurovascular Dysfunction, BBB Disruption and Oxidative Stress in Ischemic Brain

脑缺血再灌注过程中产生的氧化应激是导致血脑损伤的重要事件 血脑屏障（BBB）破坏，伴继发性血管源性水肿和梗死灶出血性转化 脑组织，限制了用血栓溶解剂进行组织再灌注的益处。我们已经证明 锰超氧化物歧化酶（SOD 2-/+）缺陷小鼠轻度脑缺血（30分钟） 引起与基质金属蛋白酶（MMP）活化相关的延迟（>24小时）BBB破坏， 炎症和高脑出血率。我们的初步研究进一步表明， 内皮细胞NADPH氧化酶的过度表达与出血性脑血管病的形成有关。 在SOD 2-/+小鼠中的转化和脑出血（ICH），以及抑制NADPH 氧化酶显著减少ICH和梗死体积。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信号通路的表达导致 神经血管功能障碍、BBB破坏和MMP-9活化引起的内皮细胞死亡。我们的目标是 使用这种新开发的具有延迟BBB破坏的SOD 2-/+小鼠模型来测试这一假设。我们 我相信这些是新的研究，将提供深入了解治疗的机会，以尽量减少氧化 急性缺血性卒中患者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.