Inhibition of RHO-kinase depends on factors that modify endothelial permeability

The endothelium that lines the inner surface of all vessels plays the role of a barrier and regulates the permeability of vascular walls that control the exchange between circulating blood and tissue fluids. The disturbance of normal functions (endothelial dysfunction) can be caused both internal and external factors. Endothelial dysfunction is characterized by the increasing permeability of the vascular wall, as is observed in many human diseases. The dysfunction is also a side effect observed during the treatment of cancer with mitosis-blocking drugs. The depolymerization of microtubules is the first step in the cascade of reactions that lead to the dysfunction of the endothelial barrier. This stage is general and does not depend on the nature of factors that provoke the dysfunction. To develop the strategy to prevent barrier dysfunction, the purpose of the present work was to elucidate the extent to which the endothelial cell cytoskeleton reaction will be universal in the barrier dysfunction. We found that cascade events that followed microtubule depolymerization and associated with the activity of Rho-Rho-kinases have features that depend on the factor that provokes barrier dysfunction. With Rho-kinase activity, suppressed actin filament behavior is independent of the agent that caused the dysfunction. Conversely, the microtubule system reacts differently to the treatment and depends on the factor that provokes the dysfunction. Under the suppression of Rho-kinase activity, unlike thrombin, nocodazole destroys both dynamic and stable microtubules. Thus, independent of the dysfunction-provoking factor, initial stages of the dysfunction associated with the depolymerization of microtubules appeared to be unchangeable. Consequently, the endothelial cell defense strategy should be based on the application of cytoplasmatic microtubule protectors, rather than the use of factors involved in the cascade at later stages, as we had previously assumed.