Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality

Sascha David, Chandra C. Ghosh, Philipp Kümpers, Nelli Shushakova, Paul van Slyke, Eliyahu V. Khankin, S. Ananth Karumanchi, Dan Dumont, Samir M. Parikh

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ∼70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% (n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% (n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.

Original languageEnglish (US)
Pages (from-to)L851-L862
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume300
Issue number6
DOIs
StatePublished - Jun 2011
Externally publishedYes

Keywords

  • Acute lung injury
  • Angiopoietins
  • Endothelial permeability
  • Endotoxin
  • Sepsis
  • Tie-2/TEK
  • Vascular leakage
  • Vasculotide

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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