Cdc42 regulates adherens junction stability and endothelial permeability by inducing α-catenin interaction with the vascular endothelial cadherin complex

Abstract

The endothelial adherens junctions (AJs) consist of trans-oligomers of membrane spanning vascular endothelial (VE)-cadherin proteins, which bind β-catenin through their cytoplasmic domain. β-Catenin in turn binds α-catenin and connects the AJ complex with the actin cytoskeleton. We addressed the in vivo effects of loss of VE-cadherin interactions on lung vascular endothelial permeability and the role of specific Rho GTPase effectors in regulating the increase in permeability induced by AJ destabilization. We used cationic liposomes encapsulating the mutant of VE-cadherin lacking the extracellular domain (ΔEXD) to interfere with AJ assembly in mouse lung endothelial cells. We observed that lung vascular permeability (quantified as microvessel filtration coefficient [Kf,c]) was increased 5-fold in lungs expressing ΔEXD. This did not occur to the same degree on expression of the VE-cadherin mutant, ΔEXDΔβ, lacking the β-catenin-binding site. The increased vascular permeability was the result of destabilization of VE-cadherin homotypic interaction induced by a shift in the binding of β-catenin from wild-type VE-cadherin to the expressed ΔEXD mutant. Because ΔEXD expression in endothelial cells activated the Rho GTPase Cdc42, we addressed its role in the mechanism of increased endothelial permeability induced by AJ destabilization. Coexpression of dominant-negative Cdc42 (N17Cdc42) prevented the increase in Kf,c induced by ΔEXD. This was attributed to inhibition of the association of α-catenin with the ΔEXD-β-catenin complex. The results demonstrate that Cdc42 regulates AJ permeability by controlling the binding of α-catenin with β-catenin and the consequent interaction of the VE-cadherin/catenin complex with the actin cytoskeleton. © 2006 American Heart Association, Inc.