Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier.
Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier.
复制标题
DOI：
10.1161/strokeaha.115.009099
复制
发表时间：
2015-06
期刊：
影响因子：
8.3
通讯作者：
Ren X
中科院分区：
文献类型：
--
作者：
Doll DN;Hu H;Sun J;Lewis SE;Simpkins JW;Ren X
血脑屏障（BBB）是一种选择性通透的脑血管内皮屏障，它维持着外周和中枢神经系统（CNS）之间的内稳态。血脑屏障的破坏是缺血性中风的一个后果，并且感染/炎症会改变血脑屏障的通透性，但导致这种血脑屏障改变的复杂细胞和分子变化需要被阐明以确定其机制。
在体内对小鼠大脑中动脉短暂闭塞（tMCAO）后，感染模拟物（脂多糖，LPS）对梗死体积、血脑屏障通透性、浸润的中性粒细胞和功能结果的影响；在体外对受到LPS刺激的脑血管内皮细胞（CVECs）进行线粒体评估；在体外和体内对线粒体进行药理学抑制对血脑屏障通透性的影响；线粒体抑制剂对tMCAO后血脑屏障通透性、梗死体积和功能结果的影响。
我们在此报道，在小鼠tMCAO后，LPS会使缺血性中风的结果恶化，并增加血脑屏障的通透性。此外，我们阐明了一种新的机制，即线粒体功能受损是血脑屏障通透性增加的原因，证据如下：LPS诱导CVECs中氧化磷酸化和呼吸链复合物亚基表达的降低，在体外CVECs以及体内动物模型中通过对线粒体功能进行药理学抑制诱导血脑屏障通透性受损，以及在抑制线粒体功能后tMCAO小鼠的中风结果恶化。
我们得出结论，线粒体是血脑屏障通透性的关键因素。这些新的发现提示了一种通过调节内皮细胞线粒体来治疗缺血性中风的潜在新策略。
The blood-brain barrier (BBB) is a selectively permeable cerebrovascular endothelial barrier that maintains homeostasis between the periphery and central nervous system (CNS). BBB disruption is a consequence of ischemic stroke and BBB permeability can be altered by infection/inflammation, but the complex cellular and molecular changes that result in this BBB alteration need to be elucidated to determine mechanisms. Infection mimic (LPS) challenge on infarct volume, BBB permeability, infiltrated neutrophils and functional outcomes following murine transient middle cerebral artery occlusion (tMCAO) in vivo; mitochondrial evaluation of cerebrovascular endothelial cells (CVECs) challenged by LPS in vitro; pharmacological inhibition of mitochondria on BBB permeability in vitro and in vivo; the effects of mitochondrial inhibitor on BBB permeability, infarct volume and functional outcomes following tMCAO. We report here that LPS worsens ischemic stroke outcome and increases BBB permeability following tMCAO in mice. Further, we elucidate a novel mechanism that compromised mitochondrial function accounts for increased BBB permeability as evidenced by: LPS-induced reductions in oxidative phosphorylation and subunit expression of respiratory chain complexes in CVECs, a compromised BBB permeability induced by pharmacological inhibition of mitochondrial function in CVECs in vitro and in an in vivo animal model, and worsened stroke outcomes in tMCAO mice following inhibition of mitochondrial function. We concluded that mitochondria are key players in BBB permeability. These novel findings suggest a potential new therapeutic strategy for ischemic stroke by endothelial cell mitochondrial regulation.