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Research Article |
1 Department of Experimental Immunohematology, CLB and Laboratory for Clinical
and Experimental Immunology, Academic Medical Center, Plesmanlaan 125 1066 CX,
Amsterdam
2 Division of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066
CX Amsterdam, The Netherlands
* Author for correspondence (e-mail: p_hordijk{at}clb.nl )
The integrity of the endothelium is dependent on cell-cell adhesion, which is mediated by vascular-endothelial (VE)-cadherin. Proper VE-cadherin-mediated homotypic adhesion is, in turn, dependent on the connection between VE-cadherin and the cortical actin cytoskeleton. Rho-like small GTPases are key molecular switches that control cytoskeletal dynamics and cadherin function in epithelial as well as endothelial cells. We show here that a cell-penetrating, constitutively active form of Rac (Tat-RacV12) induces a rapid loss of VE-cadherin-mediated cell-cell adhesion in endothelial cells from primary human umbilical veins (pHUVEC). This effect is accompanied by the formation of actin stress fibers and is dependent on Rho activity. However, transduction of pHUVEC with Tat-RhoV14, which induces pronounced stress fiber and focal adhesion formation, did not result in a redistribution of VE-cadherin or an overall loss of cell-cell adhesion. In line with this observation, endothelial permeability was more efficiently increased by Tat-RacV12 than by Tat-RhoV14.
The loss of cell-cell adhesion, which is induced by Tat-RacV12, occurred in
parallel to and was dependent upon the intracellular production of reactive
oxygen species (ROS). Moreover, Tat-RacV12 induced an increase in tyrosine
phosphorylation of a component the VE-cadherin-catenin complex, which was
identified as 
-catenin. The functional relevance of this signaling
pathway was further underscored by the observation that endothelial cell
migration, which requires a transient reduction of cell-cell adhesion, was
blocked when signaling through ROS was inhibited.
In conclusion, Rac-mediated production of ROS represents a previously unrecognized means of regulating VE-cadherin function and may play an important role in the (patho)physiology associated with inflammation and endothelial damage as well as with endothelial cell migration and angiogenesis.
Key words: pHUVEC, Rac, Rho, Reactive oxygen species, VE-cadherin
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