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1 University of Wuerzburg, Institute of Anatomy and Cell Biology, Wuerzburg, Germany
2 School of Medicine, University of California, Department of Human Physiology and Membrane Biology, Davis, CA, USA
* To whom correspondence should be addressed. E-mail: jenswaschke{at}gmx.de.
We tested the hypothesis that the equilibrium between F- and G-actin in endothelial cells modulates the integrity of the actin cytoskeleton and is important for the maintenance of endothelial barrier functions in vivo and in vitro. We used the actin-depolymerizing agent cytochalasin D, and jasplakinolide, an actin filament (F-actin) stabilizing and promoting substance to modulate the actin cytoskeleton. Low doses of jasplakinolide (0.1 µM) which we have previously shown to reduce the permeability-increasing effect of cytochalasin D had no influence on resting permeability of single-perfused mesenteric microvessels in vivo as well as on monolayer integrity. F-actin content of cultured endothelial cells remained unchanged. In contrast, higher doses (10µM) of jasplakinolide increased permeability (hydraulic conductivity) to the same extent as cytochalasin D and induced formation of intercellular gaps in cultured myocardial endothelial (MyEnd) cell monolayers. This was accompanied by a 34 % increase of F-actin and pronounced disorganisation of the actin cytoskeleton in MyEnd cells. Furthermore, we tested whether an increase of cAMP by forskolin and rolipram would prevent the cytochalasin D-nduced barrier breakdown. Conditions that increase intracellular cAMP failed to block the cytochalasin D-induced permeability increase in vivo and the reduction of VE-cadherin-mediated adhesion in vitro. Taken together these data support the hypothesis that the state of polymerization of the actin cytoskeleton is critical for maintenance of endothelial barrier functions and both depolymerization by cytochalasin D and hyperpolymerization of actin by jasplakinolide resulted in an increase of microvessel permeability in vivo. However, cAMP which is known to support endothelial barrier functions seems to work by mechanisms other than stabilizing F-actin.
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