title: The synthetic tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis.
abstract: BACKGROUND
  Angiopoietin-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.
  
  
  METHODS
  Polymicrobial 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.
  
  
  RESULTS
  Systemic 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).
  
  
  CONCLUSIONS
  We 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.
authors: Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Strasse 33, Münster 48149 Germany. philipp.kuempers@ukmuenster.de
authors: Philipp
authors: P
authors: Kumpers
authors: Faikah
authors: F
authors: Gueler
authors: Sascha
authors: S
authors: David
authors: Paul Van
authors: PV
authors: Slyke
authors: Daniel J
authors: DJ
authors: Dumont
authors: Joon-Keun
authors: JK
authors: Park
authors: Clemens L
authors: CL
authors: Bockmeyer
authors: Samir M
authors: SM
authors: Parikh
authors: Hermann
authors: H
authors: Pavenstadt
authors: Hermann
authors: H
authors: Haller
authors: Nelli
authors: N
authors: Shushakova
mesh_terms: D000005:Abdomen / Q000473:pathology; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000627:therapeutic use; D010529:Peritoneal Cavity / Q000473:pathology; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000819:agonists* / Q000138:chemical synthesis / Q000502:physiology*; D042787:Receptor, TIE-2; D018805:Sepsis / Q000378:metabolism / Q000401:mortality* / Q000517:prevention & control*
chemical_list: D010455:Peptides; D011092:Polyethylene Glycols; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse