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Further investigation revealed that β-catenin Y142 phosphorylation was required for AGEs-mediated β-catenin nuclear translocation, and this nuclear-located β-catenin subsequently activated the TCF/LEF pathway. This pathway promotes the transcription of the Wnt target, ADAM10 (a disintegrin and metalloprotease 1, which mediates VE-cadherin shedding and leads to further impairment of AJs. In summary, our study showed the role of β-catenin Y654 and Y142 phosphorylation in AGEs-mediated endothelial hyperpermeability through VE-cadherin/β-c