Abstract
BackgroundAfter cerebral injury blood-brain barrier disruption significantly impairs brain homeostasis. Volatile anesthetics have been shown to be protective in ischemia-reperfusion injury scenarios. Their impact on brain endothelial cells after hypoxia-reoxygenation (H/R) has not yet been studied in detail.MethodsRat brain endothelial cells (RBE4) were exposed to severe hypoxia and reoxygenated in air in the presence or absence of sevoflurane. Changes in dextran permeability and architecture of the cellular junctional proteins ZO-1 and β-catenin were measured. To determine necrosis and apoptosis rate DNA content, LDH release and caspase activity were quantified. The role of vascular endothelial growth factor (VEGF) as an inflammatory mediator increasing vascular permeability was assessed. At the same time, it was evaluated if sevoflurane effects are mediated through VEGF. Results were analyzed by unpaired t-tests or one way-analysis of variance followed by Bonferroni’s correction.ResultsH/R led to a 172% increase in permeability (p<0.001), cell swelling and qualitatively but not quantitatively modified expression of ZO-1, β-catenin and F-actin. In the presence of sevoflurane during reoxygenation, barrier function improved by 96% (p = 0.042) in parallel to a decrease of the cell size and less re-arranged junction proteins and F-actin. Sevoflurane-induced improvement of the barrier function could not be explained on the level of necrosis or apoptosis as they remained unchanged independent of the presence or absence of the volatile anesthetic. Increased expression of VEGF after H/R was attenuated by sevoflurane by 34% (p = 0.004). Barrier protection provided by sevoflurane was similar to the application of a blocking VEGF-antibody. Furthermore, the protective effect of sevoflurane was abolished in the presence of recombinant VEGF.ConclusionsIn H/R-induced rat brain endothelial cell injury sevoflurane maintains endothelial barrier function through downregulation of VEGF, which is a key player not only in mediating injury, but also with regard to the protective effect of sevoflurane.
Highlights
The blood-brain barrier (BBB) strictly controls and regulates molecular exchange between the cerebral and vascular compartments, thereby safeguarding cerebral function [1]
Sevofluraneinduced improvement of the barrier function could not be explained on the level of necrosis or apoptosis as they remained unchanged independent of the presence or absence of the volatile anesthetic
Increased expression of vascular endothelial growth factor (VEGF) after H/R was attenuated by sevoflurane by 34% (p = 0.004)
Summary
The blood-brain barrier (BBB) strictly controls and regulates molecular exchange between the cerebral and vascular compartments, thereby safeguarding cerebral function [1]. In brain injury, this early phase of brain edema formation involves an increase of vascular endothelial growth factor (VEGF) [5], one of the most potent permeability factors [6] [7]. VEGF directly modifies endothelial cell junctions [8, 9] [10] as well as the actin cytoskeleton [11] and may promote further disruption of the blood-brain barrier, leading to neuronal malfunction [12]. Volatile anesthetics have been shown to be protective in ischemia-reperfusion injury scenarios. Their impact on brain endothelial cells after hypoxia-reoxygenation (H/R) has not yet been studied in detail
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