The activation of β-catenin in cerebral endothelial cells alleviates neurovascular damage after ischemic stroke

Document Type

Conference Proceeding

Publication Date

2-1-2025

Publication Title

Stroke

Abstract

Background: Stroke induced disruption of the blood-brain barrier (BBB) exacerbates neurovascular damage. Emerging data show that deficiency of endothelial β-catenin contributes to stroke-induced BBB disruption and hemorrhagic brain injury. However, whether activation of β-catenin in cerebral endothelial cells (CECs) alleviates stroke induced neurovascular damage is unknown. Using transgenic mice with CEC specific activation of β-catenin, the present study investigated whether enhancement of CEC β-catenin activity reduces neurovascular damage after stroke. Methods: A transgenic mouse line with inducible CEC specific expression of a stable β-catenin mutant (CEC-Ctnnb1 mice) was generated by crossing Slco1c1-Cre mouse with Ctnnb1 mouse. Tamoxifen (TAM) was injected for 5 days to active Cre recombinase. Western blot was performed to verify β-catenin activation in the adult CEC-Ctnnb1 and their wild-type (WT) littermates (n=6/group) after termination of TAM. Male CEC-Ctnnb1 and WT mice treated with TAM were subjected to permanent middle cerebral artery occlusion (MCAO, n=10/group). Neurological function was evaluated with modified neurological severity score and foot-fault test at 1 and 7 days after MCAO. Brain tissues were processed for evaluations on infarct volume, gross hemorrhage, vascular leakage, and tight junction protein expression. Results: Immunohistochemistry and Western blot analyses revealed nuclear β-catenin expression specifically in the CECs of CEC-Ctnnb1 mice, but not in the WT mice, which was associated with significant elevation of β-catenin regulated the tight junction proteins, claudin 5 and ZO-1 by ∼2 fold, compared to the WT mice. The ischemic CEC-Ctnnb1 mice exhibited significantly reduced infarct volume (16±5% vs 25±6% in WT), which was associated with a robust reduction of neurological deficits by 35% and 53% at 1 and 7 days after MCAO, respectively. Compared to the WT ischemic mice, ischemic CEC-Ctnnb1 mice exhibited significant increases of vascular claudin-5 by 45% and ZO-1 by 31%, which were associated with a significant reduction of extravascular fibrin deposition (5±1/mm vs 8±1/mm in WT). However, the incidence of gross hemorrhage was not different between the groups.Conclusions: The activation of β-catenin in CECs attenuates ischemic brain damage by alleviating stroke induced cerebrovascular disruption. Thus, targeting endothelial β-catenin signal may be a promising strategy for treatment of acute ischemic stroke.

Volume

56

Issue

Suppl_1

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