EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke
Benjamin Okyere, … , John B. Matson, Michelle H. Theus
Benjamin Okyere, … , John B. Matson, Michelle H. Theus
Published February 3, 2020; First published November 5, 2019
Citation Information: J Clin Invest. 2020;130(2):1024-1035. https://doi.org/10.1172/JCI131493.
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Research Article Neuroscience Vascular biology

EphA4/Tie2 crosstalk regulates leptomeningeal collateral remodeling following ischemic stroke

Abstract

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.

Authors

Benjamin Okyere, William A. Mills III, Xia Wang, Michael Chen, Jiang Chen, Amanda Hazy, Yun Qian, John B. Matson, Michelle H. Theus

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Figure 1

Increased CBF and reduced infarct volume in EC-specific KO mice following pMCAO.

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Increased CBF and reduced infarct volume in EC-specific KO mice followin...
(A) Laser doppler images before and after pMCAO. Panel shows representative images from EphA4fl/fl WT and EphA4fl/fl/Tie2::Cre KO mice before and after pMCAO. (B) Quantified analysis shows increased CBF in KO compared with WT mice; n = 7–10. (C) Representative serial Nissl images of 3 bregma levels in WT and (D) KO mice 1 day after pMCAO. (E) Quantified infarct volume shows a significant reduction in infarct volume in KO compared with WT mice; n = 6. (F) Rotarod assessment of WT and KO mice. KO mice performed significantly better than WT mice 3 and 7 days after stroke. (G) NSS and (H) NOR were analyzed 3–14 days after pMCAO. Two-way ANOVA with Bonferroni’s post hoc test; n = 9–17. *P < 0.05, ****P < 0.0001 compared with corresponding WT mice; ####P < 0.0001 compared with corresponding sham mice. White dotted lines in A indicate standardized ROI used for CBF quantification of each sample.