Abstract
Endothelial hyperpermeability is the initial event in the development of diabetic microvascular complications, and advanced glycation end products (AGEs) are suggested to cause much of the endothelial hyperpermeability associated with diabetes mellitus, but the molecular mechanism remains to be characterized. β-catenin reportedly plays dual functions in maintaining normal endothelial permeability by serving both as an adhesive component and a signal transduction component. Here, we found that AGEs induced the phosphorylation of β-catenin at residues Y654 and Y142 and the endothelial hyperpermeability was reversed when the two residues were blocked. In mechanism, phosphorylation of Y654 was blocked by Src inactivation, whereas phosphorylation of Y142 was reduced by a focal adhesion kinase inhibitor. β-catenin Y654 phosphorylation induced by AGEs facilitated the dissociation of vascular endothelial (VE)-cadherin/β-catenin and the impairment of adherens junctions (AJs), whereas β-catenin Y142 phosphorylation favoured the dissociation of β-catenin and α-catenin. 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 10), 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-catenin/α-catenin dissociation and up-regulation of ADAM10, thereby advancing our understanding of the underlying mechanisms of AGEs-induced microvascular hyperpermeability.