Background and Goal of Study: Hemorrhagic shock (HS) is associated with acute kidney injury (AKI) and increased mortality. Previously, we showed that targeting the endothelial angiopoietin/Tie2 system, which is involved in microvascular leakage, reduced HS-induced vascular leakage and restored microcirculatory perfusion in the cremaster. We hypothesized that the Tie2 agonist, vasculotide (VT), also restores renal perfusion as first step in prevention of AKI.
Materials and Methods: HS was induced in rats by blood withdrawal till a MAP of 30mmHg. After 1 hour, rats received VT or PBS as control, followed by fluid resuscitation for 4 additional hours to maintain MAP>50mmHg. Microcirculatory perfusion was measured in the cremaster muscle using intravital microscopy (n=10 per group) and in the kidney using contrast echography (n=5 per group). Renal perfusion was calculated by multiplying microvascular filling velocity and microvascular blood volume.
Results and Discussion: HS was characterized by a significant drop in MAP and heart rate and the development of metabolic acidosis. HS reduced the number of perfused capillaries (5±2 vs 11±2, P<0.0001) and increased non-perfused capillaries (10±2 vs 5±1, P<0.0001) in the cremaster compared to sham rats. Fluid resuscitation partly restored cremaster perfusion (perfused 8±2 P<0.001, non-perfused 8±3, P<0.01). HS decreased renal microvascular filling velocity (0.5±0.3 vs 1.0±0.3 sec-1, P<0.01) without affecting microvascular blood volume (197±188 vs 390±202 a.u., P=0.25), resulting in decreased renal perfusion (61±20 vs 334±61, P<0.01) compared to sham rats. Fluid resuscitation restored renal perfusion (175±27, P<0.05). 
Administration of VT had no effect on systemic hemodynamics. VT restored microcirculatory perfusion in the cremaster during fluid resuscitation compared to untreated HS rats (perfused 10±3 vs 8±2, P=0.07, non-perfused 6±2 vs 8±3 P<0.05). Interestingly, one hour following fluid resuscitation microvascular blood volume (788±476 vs 253±98 a.u., P<0.001) and renal perfusion (471±243 vs 188±62, P<0.01) were higher in VT compared to untreated HS rats, but this effect abolished over time (230±98 vs 175±21, P=1.0).
Conclusion(s): Targeting Tie2 with Vasculotide restored microcirculatory perfusion in the cremaster and kidney following hemorrhagic shock and fluid resuscitation. Future studies will focus on targeting Tie2 as therapeutic target to prevent AKI following hemorrhagic shock.

03 / Targeting Tie2 restores haemorrhagic shock-induced microcirculatory perfusion disturbances in cremaster and kidney during fluid resuscitation in rats
