EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia
EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia
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DOI：
10.1161/atvbaha.116.308620
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发表时间：
2017-05-01
影响因子：
8.7
通讯作者：
Vajkoczy, Peter
中科院分区：
文献类型：
--
作者：
Ghori, Adnan;Freimann, Florian B.;Vajkoczy, Peter
脑水肿是由血脑屏障破坏引起的，是中风后的主要并发症。因此，加速和增强卒中后神经血管恢复的策略是最感兴趣的。我们的主要目的是研究ephrinB 2/EphB 4信号转导介导的血管修复和血脑屏障恢复后，轻度脑缺血occlusion/reperfusion.Approach和Results-Here，我们表明，指导分子ephrinB 2起着关键作用，脑卒中后的神经血管保护和血脑屏障恢复。在局灶性脑卒中模型中，我们在细胞、分子和功能水平上描述了脑卒中引起的脑血管损伤及其随后的内源性修复。EphrinB 2及其酪氨酸激酶受体EphB 4在中风后早期被内皮细胞和血管周围支持细胞上调，与它们在神经血管恢复期间的重新组装平行。使用逆转录病毒和药理学方法，我们表明，ephrinB 2/EphB 4信号的抑制抑制大脑中动脉闭塞后的神经血管修复机制，导致脑肿胀的加重。相比之下，脑缺血后ephrinB 2的激活导致周细胞募集增加和内皮细胞周细胞的相互作用，导致在一个加速的神经血管修复后ischemia. Conclusions，我们表明，减少肿胀可能会导致改善的结果，因为减少受损的脑组织。我们还确定了ephrinB 2/EphB 4信号在维持神经血管稳态中的新作用，并提供了一种新的治疗方法，以减少中风后的脑肿胀。
Objective-Cerebral edema caused by the disruption of the blood-brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood-brain barrier restoration after mild cerebral ischemia occlusion/reperfusion.Approach and Results-Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood-brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial-pericyte interaction, resulting in an accelerated neurovascular repair after ischemia.Conclusions-We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.