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Requirement of Rac activity for maintenance of capillary endothelial barrier properties

¹Institute of Anatomy and Cell Biology, University of Würzburg, D-97070 Würzburg; ²Department of Pharmacology and Toxicology, Albert-Ludwigs-University, D-79104 Freiburg, Germany; and ³Department of Human Physiology, University of California, Davis, California 95616

Submitted 13 March 2003 ; accepted in final form 18 September 2003

Our previous experiments indicated that GTPases, other than RhoA, are important for the maintenance of endothelial barrier integrity in both intact microvessels of rats and mice and cultured mouse myocardial endothelial (MyEnd) cell 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 the degree of inhibition of Rac by glucosylation and increased endothelial barrier permeability. In rat venular microvessels, LT (200 ng/ml) increased hydraulic conductivity from a control value of 2.5 ± 0.6 to 100.8 ± 18.7 x 10^–7 cm·s^–1·cmH₂O^–1 after 80 min. In cultured MyEnd cells exposed to LT (200 ng/ml), up to 60% of cellular Rac was glucosylated after 90 min, resulting in depolymerization of F-actin and interruptions of junctional distribution of vascular endothelial cadherin (VE-cadherin) and -catenin as well as the 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 1) modulation of actin filament polymerization and 2) acting directly on the tether between VE-cadherin and the cytoskeleton.

vascular endothelial cadherin; adherens junction; permeability; Rho proteins; actin

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