Blood-brain barrier (BBB) disruption exacerbates diffuse axonal injury (DAI), but the underlying mechanisms are not fully understood. Inactivation or deletion of erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) attenuated BBB damage and promoted tight junction formation. In this study, we aimed to investigate the role of EphA2 in the protection of BBB integrity and the relevant mechanisms involved in a rat model of DAI. Blocking activation of the EphA receptor by EphA2-Fc ameliorated axonal injury, cell apoptosis, and glial activation, protected BBB integrity and increased expression of the tight junction-associated proteins ZO-1, claudin-5 and occludin-1. In vitro BBB models established by human brain microvascular endothelial cells (HBMECs) were subjected to oxygen deprivation (OGD). Treatment with EphrinA1, which activates EphA2, exacerbated the OGD-induced destruction of permeability and integrity of the BBB models by reducing the expression of tight junction-associated proteins. However, inhibition of Rho-associated coiled coil-containing protein kinases 1 and 2 (ROCK1 and 2) abrogated all of the effects of EphrinA1 on the BBB models in vitro. In conclusion, we provide evidence that EphA2 plays an important role in the destruction of BBB integrity by decreasing the expression of tight junction proteins through the ROCK pathway.

血脑屏障（BBB）破坏加剧了弥漫性轴索损伤（DAI），但其潜在机制尚未完全了解。产生促红细胞生成素的肝癌（EPH）受体A2（EphA2）的失活或缺失减弱了BBB损伤并促进了紧密连接的形成。在这项研究中，我们旨在研究EphA2在保护BBB完整性中的作用以及DAI大鼠模型中涉及的相关机制。EphA2-Fc阻断EphA受体的活化可改善轴突损伤，细胞凋亡和神经胶质活化，从而保护BBB完整性并增强紧密连接相关蛋白ZO-1，claudin-5和occludin-1的表达。对人脑微血管内皮细胞（HBMEC）建立的体外BBB模型进行氧剥夺（OGD）。用激活EphA2的EphrinA1进行治疗，通过减少紧密连接相关蛋白的表达，加剧了OGD诱导的BBB模型通透性和完整性破坏。但是，抑制Rho相关的含线圈卷曲蛋白激酶1和2（ROCK1和2）抑制了EphrinA1对BBB模型体外的所有作用。总之，我们提供的证据表明，EphA2通过降低ROCK通路的紧密连接蛋白的表达在破坏BBB完整性中起着重要作用。