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Cardiovascular Research Institute, Departments of Surgery and Medical Physiology, Texas A&M University System Health Science Center, 702 Southwest H. K. Dodgen Loop, Temple, TX 76504, USA
VE-cadherin constitutes endothelial adherens junctions through a homophilic binding of its extracellular domain and by the anchoring of its intracellular domain to actin cytoskeleton via catenins. The aim of this study was to determine the functional importance of VE-cadherin–cytoskeleton association in the maintenance of endothelial junctional integrity. A recombinant VE-cadherin cytoplasmic domain (rVE-cad CPD) was expressed in E. coli and purified through Ni-NTA spin columns. Immunoprecipitation assays showed that rVE-cad CPD was able to bind ß-catenin in vitro and to compete with endogenous VE-cadherin for binding of ß-catenin in human umbilical vein endothelial cells. A significant increase in the transendothelial flux of albumin was observed in the endothelial cell monolayers transfected with rVE-cad CPD. Importantly, transfection of rVE-cad CPD into intact isolated coronary venules markedly elevated the albumin permeability of the venular endothelium. In addition, immunofluorescence microscopic analysis revealed a conformational change of VE-cadherin from a uniform, continuous distribution along the cell membrane under control conditions to a diffuse, stitch-like pattern after rVE-cad CPD transfection. The effects were likely due to an attenuated anchorage of endogenous VE-cadherin to the cytoskeleton, as evidenced by a decreased partitioning of VE-cadherin in the detergent-insoluble cytoskeletal pool. The results suggest that the intracellular association of VE-cadherin with ß-catenin-linked cytoskeleton is essential to the maintenance of endothelial junctional integrity and microvascular permeability.
(Received 10 July 2003;
accepted after revision 20 October 2003;
first published online 24 October 2003)
Corresponding author S. Y. Yuan: Cardiovascular Research Institute, Department of Surgery, Texas A&M University System Health Science Center, 702 Southwest H. K. Dodgen Loop, Temple, TX 76504, USA. Email: yuan{at}tamu.edu
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