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1 Institute of Anatomy and Cell Biology, University of Wuerzburg, Wuerzburg, Germany
2 Department of Human Physiology, University of California, Davis, California, USA
* To whom correspondence should be addressed. E-mail: fecurry{at}ucdavis.edu.
We demonstrated previously that inhibition of the small GTPase Rac-1 by C. sordellii lethal toxin (LT) increased the hydraulic conductivity (Lp) of rat venular microvessels and induced gap formation in cultured myocardial endothelial cells (MyEnd). In MyEnd cells we also demonstrated that both LT and cytochalasin D reduced cellular adhesion of VE-cadherincoated beads. Here we further evaluate the contribution of actin depolymerization, myosinbased contraction, and VE-cadherin linkage to the actin cytoskeleton to LT-induced permeability. The actin-depolymerizing agent cytochalasin D increased Lp in single rat mesenteric microvessels to the same extent as LT over 80 min. However, whereas the actin stabilizing agent jasplakinolide blunted the Lp increase due to cytochalasin D by 78 %, it had no effect on the LT response. This conforms to the hypothesis that the predominant mechanism whereby Rac-1 stabilizes the endothelial barrier in intact microvessels is separate from actin polymerization, and likely at the level of the VE-cadherin linkage to the actin cytoskeleton. In intact vessels, neither inhibition of contraction (butanedione-monoxime, BDM, an inhibitor of myosin ATPase) nor inhibition of Rho kinase (Y-27632) modified the response to LT, even though both inhibitors lowered resting Lp. In contrast BDM and inhibition of MLCK completely inhibited LT-induced intercellular gap formation and largely reduced the LT-induced permeability increase in MyEnd monolayers. These results support the hypothesis that the contractile mechanisms that contribute to the formation of large gaps between cultured endothelial cells exposed to inflammatory conditions do not significantly contribute to increased permeability in intact microvessels.
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