Inhibition of VE-Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability

Please cite this paper as: Sawant, Tharakan, Adekanbi, Hunter, Smythe and Childs (2011). Inhibition of VE‐Cadherin Proteasomal Degradation Attenuates Microvascular Hyperpermeability. Microcirculation18(1), 46–55. Objective: VE‐cadherin, an integral component of the adherens junction complex, is processed through the endosome–lysosome pathway and proteasome system for degradation. Our objective was to determine if inhibition of this pathway would protect against microvascular hyperpermeability. Methods: To induce VE‐cadherin degradation, we utilized a mutant VE‐cadherin protein that lacks the extracellular domain (rVE‐cad CPD). Intravital microscopy was employed to study the changes in microvascular permeability in rat mesenteric postcapillary venules. Rat lung microvascular endothelial cell (RLMEC) monolayers were utilized in parallel studies. The adherens junction integrity was determined using VE‐cadherin and β‐catenin immunofluorescence. TOPflash/FOPflash transfection and luciferase reporter assay were performed to study β‐catenin‐mediated transcriptional activation. Results: rVE‐cad CPD (2.5 μg/mL of blood volume) increased hyperpermeability significantly (p