Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity

Zhang, Shuai1; Zhao, Jing2; Sha, Wei-Meng1; Zhang, Xin-Pei1; Mai, Jing-Yuan1; Bartlett, Perry F.2; Hou, Sheng-Tao1

2023-10-01

10.1177/0271678X231209607

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM   Impact Factor & Quartile

0271-678X

1559-7016

Cerebral vasogenic edema, a severe complication of ischemic stroke, aggravates neurological deficits. However, therapeutics to reduce cerebral edema still represent a significant unmet medical need. 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.

Blood-brain barrier EphA4 stress fibers stroke vasogenic edema

SCI

English

First ; Corresponding

Endocrinology & Metabolism ; Hematology ; Neurosciences & Neurology

Endocrinology & Metabolism ; Hematology ; Neurosciences

WOS:001090307000001

SAGE PUBLICATIONS INC

NEUROSCIENCE & BEHAVIOR

Web of Science

1.Southern Univ Sci & Technol, Brain Res Ctr, Sch Life Sci, Dept Biol, Shenzhen, Peoples R China
2.Univ Queensland, Queensland Brain Inst, Brisbane, Australia

Zhang, Shuai,Zhao, Jing,Sha, Wei-Meng,et al. Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity[J]. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM,2023.

Zhang, Shuai.,Zhao, Jing.,Sha, Wei-Meng.,Zhang, Xin-Pei.,Mai, Jing-Yuan.,...&Hou, Sheng-Tao.(2023).Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity.JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM.

Zhang, Shuai,et al."Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity".JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM (2023).