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Am J Physiol Heart Circ Physiol (September 25, 2003). doi:10.1152/ajpheart.00221.2003
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Submitted on March 13, 2003
Accepted on September 18, 2003

Requirement of Rac Activity for Maintenance of Capillary Endothelial Barrier Properties

J. Waschke1*, W. Baumgartner1, R. H. Adamson2, M. Zeng2, K. Aktories3, H. Barth3, C. Wilde3, F. E. Curry2, and D. Drenckhahn1

1 Institute of Anatomy and Cell Biology, University of Wuerzburg, Wuerzburg, Germany
2 Department of Human Physiology, University of California at Davis, Davis, California, USA
3 Department of Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany

* To whom correspondence should be addressed. E-mail: jenswaschke{at}gmx.de.

Our previous experiments indicated that GTPases, other than RhoA, are important for maintenance of endothelial barrier integrity in both intact microvessels of rats and mice and cultured mouse myocardial endothelial cell (MyEnd) monolayers (J. Physiol.539: 295-308, 2002). In the present study, we inhibited the endothelial GTPase Rac by Clostridium sordellii lethal Toxin (LT) and investigated the relation between degree of inhibition of Rac by glucosylation and increased endothelial barrier permeability. In rat venular microvessels LT (200ng/ml) increased hydraulic conductivity (Lp) from control values of 2.5 ± 0.6 to 100.8 ± 18.7 x10 -7 cm/(sec cmH20) after 80 min. In cultured MyEnd cells exposed to LT (200ng/ml) up to 60% of cellular Rac was glucosylated after 90 min, resulting in depolymerization of F- actin, interruptions of junctional distribution of VE-cadherin and {beta}-catenin as well as formation of intercellular gaps. To understand the mechanism by which inhibition of Rac caused disassembly of adherens junctions, we used laser tweezers to quantify VE-cadherin-mediated adhesion. LT and cytochalasin D, an actin depolymerizing agent, both reduced adhesion of VE-cadherin-coated microbeads to the endothelial cell surface, whereas the inhibitor of Rho kinase, Y-27632, did not. Stabilization of actin filaments by jasplakinolide completely blocked the effect of cytochalasin D but not of LT on bead adhesion. We conclude that Rac regulates endothelial barrier properties in vivo and in vitro by (i) modulation of actin filament polymerization and (ii) by acting directly on the tether between VE-cadherin and the cytoskeleton.




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