Abstract
IntroductionAngiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis.MethodsPolymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls.ResultsSystemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05).ConclusionsWe provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept.
Highlights
Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a nonredundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions
We and others have shown that Angpt2 levels in plasma from critically ill patients with sepsis correlate with the extent of pulmonary vascular leakage in acute lung injury (ALI) [19], increase with the severity of acute kidney injury (AKI) [16], and independently predict mortality in the intensive care unit [14,16,20,21,22]
Vasculotide induces Tie2 posphorylation in vivo Having verified that VT induces Tie2 phosphorylation in vitro in previous work [26], we initially tested whether VT can induce Tie2 activation in vivo
Summary
Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie receptor, is a nonredundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Subsequent studies confirmed the latter hypothesis by demonstrating that either acute administration of recombinant Angpt protein or gene transfer of Angpt prevented capillary leakage, protected against subsequent acute kidney injury (AKI) and acute lung injury (ALI), and improved survival in Gram-negative murine endotoxemia [5,6,7,8,9,10,11]. We and others have shown that Angpt levels in plasma from critically ill patients with sepsis correlate with the extent of pulmonary vascular leakage in ALI [19], increase with the severity of AKI [16], and independently predict mortality in the intensive care unit [14,16,20,21,22]. Local or systemic injection of recombinant Angpt in otherwise-healthy mice is sufficient to provoke tissue edema or pulmonary vascular leakage, respectively [23,24]
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