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Genetic and Pharmacological Targeting of the EphA4/Tie2 Axis Results in Improved Pial Collateral Response following Ischemic Stroke

ABSTRACT: Background: Pial collaterals are a major determinant of patient outcome following ischemic stroke, however, targeted treatments for enhancing these blood vessels remain elusive. EphA4, a receptor tyrosine kinase, has been found to restrict the growth of these vessels, potentially through modulation of the Tie2 signaling pathway. The present study assessed the endothelial cell (EC)-specific role of EphA4 in arteriogenesis and the therapeutic potential of Vasculotide, a Tie2 agonist, after ischemic stroke. Methods: EC-specific EphA4 knockout mice and wildtype controls, as well as wildtype mice treated with vehicle or Vasculotide, were subjected to a permanent middle cerebral artery model of stroke. Infarct volume and functional recovery were assessed. Vessel painting coupled with immunohistochemistry was employed to assess collateral size and cellular changes. Bulk RNA sequencing of the pial surface was performed to identify unique transcriptional changes. Results: Deletion of EphA4 in ECs resulted in increased collateral size and accelerated cellular remodeling, which correlated with reduced infarct volume, enhanced CBF recovery, and improved performance on behavioral assessments. These effects could be replicated in wildtype mice through the administration of 3g/kg Vasculotide immediately following stroke. Treatment with 150g/kg Vasculotide provided neuroprotection and increased collateral size but lacked the robust improvements in CBF recovery and motor recovery seen in the 3g/kg treated group. Additionally, pial surfaces from 3g/kg Vasculotide and EphA4 KO mice showed significant changes in mRNA transcripts associated with the Krt5/Krt14 pathway compared to WT controls. Conclusion: The EphA4/Tie2 signaling axis mediates collateral growth and can be successfully therapeutically targeted by Vasculotide.

ORGANISM(S): Mus musculus

PROVIDER: GSE242163 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Cerebral ischemia/reperfusion injury (CI/RI), including neurological behavior deficits, cerebral infarction, blood-brain barrier (BBB) dysfunction, and neuroinflammation, et al. is a severe challenge in treatment of ischemic stroke. Traditional Chinese medicine (TCM) with the characteristics of multi-components and multi-functions for multiple targets/pathways has been historically used in the treatment of stroke and post stroke recovery in China. QiShenYiQi (QSYQ), a representative component-based Chinese medicine, is capable of reducing organ injury caused by ischemia/reperfusion via multiple mechanisms. Recently, we have previously reported that the positive action of QSYQ against the acute phase of CI/RI is partly via modulation of neuroinflammatory response. However, the effects and underlying mechanisms of QSYQ on subacute phase of CI/RI remain unknown, which are aimed to investigate in present study. The pharmacological action of QSYQ treatment on brain damage was estimated in the experimental stroke rats underwent 90 min ischemia and 8 days reperfusion by assessing the neurological and locomotor deficits, cerebral infarction, brain edema, and BBB integrity. Furthermore, we used TMT-based quantitative proteomics technology to identify significantly differentially expressed proteins following QSYQ treatment, which could give important clues for revealing the possible mechanism underlying the positive role of QSYQ in CI/RI. Besides, immunohistochemistry, western blot analysis, RT-qPCR, and rat ELISA kits were executed to further verify the accuracy of proteomics analysis results. As a consequence, we found that treatment with QSYQ (600mg/kg) for 7 days obviously improved neurological and behavioral impairment, attenuated infarct volume and brain edema, and alleviated BBB breakdown in stroke rats. Bioinformatics analysis suggested that differentially expressed protein galectin-3 mediated inflammatory response was closely related to the beneficial effect of QSYQ. Results of immunohistochemistry, western blot analysis and RT-qPCR showed that the model rats treated with QSYQ (600mg/kg) markedly downregulated the mRNA and protein expression level of galectin-3 in brain tissues compared to the untreated stroke rats. In addition, the decrease of mRNA level in brain tissues and contents in serum of TNF-α and IL-6 following QSYQ treatment were also observed. These interesting finding manifested that the effective action of QSYQ against subacute phase of CI/RI was partly via regulating galectin-3 mediated inflammatory reaction.

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Genetic and Pharmacological Targeting of the EphA4/Tie2 Axis Results in Improved Pial Collateral Response following Ischemic Stroke

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