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Brain microvascular endothelial cells (BMECs), vital for maintaining the blood-brain barrier (BBB), represent the first defense barrier for vasogenic edema. Here, we analyzed the proteomic profiles of the cultured mouse BMECs during oxygen-glucose deprivation and reperfusion (OGD\/R). Besides the extensively altered cytoskeletal proteins, ephrin type-A receptor 4 (EphA4) expressions and its activated phosphorylated form p-EphA4 were significantly increased. Blocking EphA4 using EphA4-Fc, a specific and well-tolerated inhibitor shown in our ongoing human phase I trial, effectively reduced OGD\/R-induced BMECs contraction and tight junction damage. EphA4-Fc did not protect OGD\/R-induced neuronal and astrocytic death. However, administration of EphA4-Fc, before or after the onset of transient middle cerebral artery occlusion (tMCAO), reduced brain edema by about 50%, leading to improved neurological function recovery. The BBB permeability test also confirmed that cerebral BBB integrity was well maintained in tMCAO brains treated with EphA4-Fc. Therefore, EphA4 was critical in signaling BMECs-mediated BBB breakdown and vasogenic edema during cerebral ischemia. EphA4-Fc is promising for the treatment of clinical post-stroke edema.<\/jats:p>","DOI":"10.1177\/0271678x231209607","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T19:10:10Z","timestamp":1698088210000},"page":"419-433","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":12,"title":["Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity"],"prefix":"10.1177","volume":"44","author":[{"given":"Shuai","family":"Zhang","sequence":"first","affiliation":[{"name":"Brain Research Centre, Department of Biology, School of Life Science, Southern University of Science and Technology, Shenzhen, P. R. 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