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VASCULAR BIOLOGY

VE-cadherin and β-catenin binding dynamics during histamine-induced endothelial hyperpermeability

¹Department of Surgery, School of Medicine, University of California-Davis, Sacramento, California; ²Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and ³Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Submitted 7 December 2007 ; accepted in final form 8 February 2008

β-Catenin plays an important role in the regulation of vascular endothelial cell-cell adhesions and barrier function by linking the VE-cadherin junction complex to the cytoskeleton. The purpose of this study was to evaluate the effect of β-catenin and VE-cadherin interactions on endothelial permeability during inflammatory stimulation by histamine. We first assessed the ability of a β-catenin binding polypeptide known as inhibitor of β-catenin and T cell factor (ICAT) to compete β-catenin binding to VE-cadherin in vitro. We then overexpressed recombinant FLAG-ICAT in human umbilical vein endothelial cells (HUVECs) to study its impact on endothelial barrier function controlled by cell-cell adhesions. The binding of β-catenin to VE-cadherin was quantified before and after stimulation with histamine along with measurements of transendothelial electrical resistance (TER) and apparent permeability to albumin (P_a) under the same conditions. The results showed that ICAT bound to β-catenin and competitively inhibited binding of the VE-cadherin cytoplasmic domain to β-catenin in a concentration-dependent manner. Overexpression of FLAG-ICAT in endothelial cell monolayers did not affect their basal permeability properties, as indicated by unaltered TER and P_a; however, the magnitude and duration of histamine-induced decreases in TER were significantly augmented. Likewise, the increase in P_a in the presence of histamine was exacerbated. Overexpression of FLAG-ICAT also significantly decreased the level of β-catenin-associated VE-cadherin following histamine stimulation. Taken together, these data suggest that inflammatory agents like histamine cause a transient and reversible disruption of binding between β-catenin and VE-cadherin, during which endothelial permeability is elevated.

endothelial barrier; cell-cell junction; signal transduction; inflammation