Vasculotide, an Angiopoietin-1 Mimetic, Restores Microcirculatory Perfusion and Microvascular Leakage and Decreases Fluid Resuscitation Requirements in Hemorrhagic Shock.

BACKGROUND: Microcirculatory dysfunction is associated with multiple organ failure and unfavorable patient outcome. We investigated whether therapeutically targeting the endothelial angiopoietin/Tie2 system preserves microvascular integrity during hemorrhagic shock. METHODS: Rats were treated with the angiopoietin-1 mimetic vasculotide and subjected to hemorrhagic shock and fluid resuscitation. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n = 7 per group) and Evans blue dye extravasation (n = 8 per group), respectively. The angiopoietin/Tie2 system was studied at protein and RNA level in plasma, kidneys, and lungs. RESULTS: Hemorrhagic shock significantly reduced continuously perfused capillaries (7 ± 2 vs. 11 ± 2) and increased nonperfused vessels (9 ± 3 vs. 5 ± 2) during hemorrhagic shock, which could not be restored by fluid resuscitation. Hemorrhagic shock increased circulating angiopoietin-2 and soluble Tie2 significantly, which associated with microcirculatory perfusion disturbances. Hemorrhagic shock significantly decreased Tie2 gene expression in kidneys and lungs and induced microvascular leakage in kidneys (19.7 ± 11.3 vs. 5.2 ± 3.0 µg/g) and lungs (16.1 ± 7.0 vs. 8.6 ± 2.7 µg/g). Vasculotide had no effect on hemodynamics and microcirculatory perfusion during hemorrhagic shock but restored microcirculatory perfusion during fluid resuscitation. Interestingly, vasculotide attenuated microvascular leakage in lungs (10.1 ± 3.3 µg/g) and significantly reduced the required amount of volume supplementation (1.3 ± 1.4 vs. 2.8 ± 1.5 ml). Furthermore, vasculotide posttreatment was also able to restore microcirculatory perfusion during fluid resuscitation. CONCLUSIONS: Targeting Tie2 restored microvascular leakage and microcirculatory perfusion and reduced fluid resuscitation requirements in an experimental model of hemorrhagic shock. Therefore, the angiopoietin/Tie2 system seems to be a promising target in restoring microvascular integrity and may reduce organ failure during hemorrhagic shock.

EEG sensorimotor correlates of translating sounds into actions.

Understanding the actions of others is a necessary foundational cornerstone for effective and affective social interactions. Such understanding may result from a mapping of observed actions as well as heard sounds onto one's own motor representations of those events. To examine the electrophysiological basis of action-related sounds, EEG data were collected in two studies from adults who were exposed to auditory events in one of three categories: action (either hand- or mouth-based sounds), non-action (environmental sounds), and control sounds (scrambled versions of action sounds). In both studies, triplets of sounds of the same category were typically presented, although occasionally, to ensure an attentive state, trials containing a sound from a different category were presented within the triplet and participants were asked to respond to this oddball event either covertly in one study or overtly in another. Additionally, participants in both studies were asked to mimic hand- and mouth-based motor actions associated with the sounds (motor task). Action sounds elicited larger EEG mu rhythm (8-13 Hz) suppression, relative to control sounds, primarily over left hemisphere, while non-action sounds showed larger mu suppression primarily over right hemisphere. Furthermore, hand-based sounds elicited greater mu suppression over the hand area in sensorimotor cortex compared to mouth-based sounds. These patterns of mu suppression across cortical regions to different categories of sounds and to effector-specific sounds suggest differential engagement of a mirroring system in the human brain when processing sounds.