EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke

Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the endothelium, although the underlying molecular mechanisms remain under investig...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-02, Vol.130 (2), p.1024-1035
Main Authors: Okyere, Benjamin, Mills, 3rd, William A, Wang, Xia, Chen, Michael, Chen, Jiang, Hazy, Amanda, Qian, Yun, Matson, John B, Theus, Michelle H
Format: Article
Language:English
Subjects:
AKT protein
Animals
Biomedical research
Blood flow
Brain Ischemia - genetics
Brain Ischemia - metabolism
Cerebral blood flow
Clonal deletion
Endothelial cells
Endothelium
EphA4 protein
Ischemia
Kinases
Meninges
Mice
Mice, Transgenic
Molecular modelling
Patients
Peptides
Phenols (Class of compounds)
Protein-tyrosine kinase receptors
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Receptor, EphA4 - genetics
Receptor, EphA4 - metabolism
Receptor, TIE-2 - genetics
Receptor, TIE-2 - metabolism
Recovery of function
Rodents
Signal Transduction
Stroke
Stroke - genetics
Stroke - metabolism
Stroke - pathology
Therapeutic targets
Tyrosine
Vascular Remodeling
Veins & arteries
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Summary:Leptomeningeal anastomoses or pial collateral vessels play a critical role in cerebral blood flow (CBF) restoration following ischemic stroke. The magnitude of this adaptive response is postulated to be controlled by the endothelium, although the underlying molecular mechanisms remain under investigation. Here we demonstrated that endothelial genetic deletion, using EphA4fl/fl/Tie2-Cre and EphA4fl/fl/VeCahderin-CreERT2 mice and vessel painting strategies, implicated EphA4 receptor tyrosine kinase as a major suppressor of pial collateral remodeling, CBF, and functional recovery following permanent middle cerebral artery occlusion. Pial collateral remodeling is limited by the crosstalk between EphA4-Tie2 signaling in vascular endothelial cells, which is mediated through p-Akt regulation. Furthermore, peptide inhibition of EphA4 resulted in acceleration of the pial arteriogenic response. Our findings demonstrate that EphA4 is a negative regulator of Tie2 receptor signaling, which limits pial collateral arteriogenesis following cerebrovascular occlusion. Therapeutic targeting of EphA4 and/or Tie2 represents an attractive new strategy for improving collateral function, neural tissue health, and functional recovery following ischemic stroke.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI131493