The endothelium as target to restore vascular leakage and microcirculatory perfusion after hemorrhagic shock

Hemorrhagic shock causes an immediate decrease in microcirculatory perfusion, which cannot be restored by standard therapy with fluids and blood products. The disturbance in microcirculatory perfusion is suggested to be the underlying cause of multiple organ failure, leading to increased mortality. To date, additional treatment strategies to restore microcirculatory perfusion following hemorrhagic shock are lacking. The endothelium is a semi-permeable barrier that covers the inner layer of the microvasculature, where it tightly regulates the exchange of fluids, nutrients and waste products between blood and tissue. In this thesis, we propose the microvascular endothelium as central regulator of hemorrhagic shock-induced microcirculatory perfusion disturbances. We investigated the effect of hemorrhagic shock and fluid resuscitation on endothelial barrier function and microcirculatory perfusion. Subsequently, we investigated which molecular mechanisms are of interest as target to reduce microvascular leakage and restore microcirculatory perfusion following hemorrhagic shock. Due to the central role of the endothelium, we propose the endothelial angiopoietin/Tie2 system, a key regulator of endothelial barrier function, as target to reduce microvascular leakage following hemorrhagic shock. The angiopoietin/Tie2 system consists of several components, of which the ligands angiopoietin-1 and angiopoietin-2 and the Tie2 receptor are mostly investigated. Under healthy conditions, angiopoietin-1 binds to the Tie2 receptor which subsequently leads to activation of the downstream pathway, thereby maintaining endothelial barrier function. A stress response, such as inflammation, excessively releases angiopoietin-2 which competitively binds the Tie2 receptor, blocking activation of the Tie2 receptor and disrupting endothelial barrier function. In this thesis, we investigated the effect of dysregulation of the angiopoietin/Tie2 system on microvascular integrity in mice. Subsequently, with the use of a rat model representing hemorrhagic shock and fluid resuscitation, we investigated whether restoring the imbalance in the angiopoietin/Tie2 system could reduce microvascular leakage and thereby restore microcirculatory perfusion following hemorrhagic shock and fluid resuscitation. Finally, we investigated whether there are sex-related differences in the regulation of the angiopoietin/Tie2 system.