Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells

Endothelial cell (EC) junctions regulate in large part the integrity and ba rrier function of the vascular endothelium. Advanced glycation end-products (AGES), the irreversibly formed reactive derivatives of non-enzymic glucos e-protein condensation reactions, are strongly implicated in endothelial dy sfunction that distinguishes diabetes- and aging-associated vascular compli cations. The aim of the present study was to determine whether AGES affect EC lateral junction proteins, with particular regard to the vascular endoth elial cadherin (VE-cadherin) complex. Our results indicate that AGE-modifie d BSA (AGE-BSA), a prototype of advanced glycated proteins, disrupts the VE -cadherin complex when administered to ECs. AGE-BSA, but not unmodified BSA , was found to induce decreases in the levels of VE-cadherin, beta -catenin and gamma -catenin in the complex and in total cell extracts, as well as a marked reduction in the amount of VE-cadherin present at the cell surface. In contrast, the level of platelet endothelial cell adhesion molecule-1 (P ECAM-1), which is located at lateral junctions, was not altered. Supplement ation of the cellular antioxidative defences abolished these effects. Final ly, the loss of components of the VE-cadherin complex was correlated with i ncreases in vascular permeability and in EC migration. These findings sugge st that some of the AGE-induced biological effects on the endothelium. coul d be mediated, at least in part, by the weakening of intercellular contacts caused by decreases in the amount of VE-cadherin present.