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

Abstract

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.

Serum Angiopoietin‐2 Predicts Mortality and Kidney Outcomes in Decompensated Cirrhosis

“…Survival Probability syndrome, and disseminated intravascular coagulation, Angpt-2 upregulation and Tie2 inhibition have been linked to thrombocytopenia, increased INR, elevated D-dimer, overexpression of pro-inflammatory cytokines, multisystem organ dysfunction (e.g., AKI), decreased systemic circulating blood pressure, and ultimately poorer survival; conversely, interventions to restore or enhance Tie2 signaling not only ameliorate these abnormalities but also improve survival. (16,18,23,42) Strikingly, this same constellation of features is present among patients with decompensated cirrhosis and ACLF. (10,14,29,43,44) Although there are no studies, to our knowledge, specifically examining Angpt-2/Tie2 interventions in combined liver-kidney injury animal models, our prospective human findings suggest that this pathway may be similarly important in HRS/AKI and cirrhosis.…”

“…As a cell‐surface receptor modulated by secreted ligands, Tie2 and Angiopoietins constitute a highly promising set of candidate drug targets for human disease. In experimental models of sepsis, systemic inflammatory syndrome, and disseminated intravascular coagulation, Angpt‐2 upregulation and Tie2 inhibition have been linked to thrombocytopenia, increased INR, elevated D‐dimer, overexpression of pro‐inflammatory cytokines, multisystem organ dysfunction (e.g., AKI), decreased systemic circulating blood pressure, and ultimately poorer survival; conversely, interventions to restore or enhance Tie2 signaling not only ameliorate these abnormalities but also improve survival . Strikingly, this same constellation of features is present among patients with decompensated cirrhosis and ACLF .…”

In vitro endothelial hyperpermeability occurs early following traumatic hemorrhagic shock

“…Current knowledge regarding hemorrhagic shock-induced hyperpermeability is restricted to animal studies [14][15][16][17][18] or in vitro studies investigating the effect of rodent plasma on endothelial barrier function [19]. Animal studies showed an early increase in endothelial permeability following hemorrhagic shock [14,15], which even further increased following fluid resuscitation [16][17][18].…”

Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats

“…Vasculotide, an angiopoietin-1 mimetic, is a recently introduced drug that functions by promoting Tie2 phosphorylation and subsequently restores or promotes endothelial stability as shown by reduced vascular leakage in animal models of sepsis, 13 acute kidney 14 or lung injury, 15 and haemorrhagic shock. 16 Although patient studies also suggested a possible important role of the angiopoietin/Tie2 system in CPB patients, this has not been confirmed using a therapeutic strategy. 4,7,9e12 We therefore aimed to investigate the relationship between Tie2 regulation and microcirculatory perfusion in a rat CPB model.…”