Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity

Joshua S Davis,Dianne P Stephens,David S Celermajer,Tsin W Yeo,Kim A Piera,Nicholas M Anstey,Tonia Woodberry

doi:10.1186/cc9020

Abstract

IntroductionAngiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Ang-2 is raised in severe sepsis but the mechanisms underlying this are not known. Nitric oxide (NO) inhibits WPB exocytosis, and bioavailability of endothelial NO is decreased in sepsis. We hypothesized that endothelial NO bioavailability would be inversely correlated with ang-2 concentrations in sepsis.MethodsPlasma ang-2, vascular endothelial growth factor (VEGF) and endothelial-active cytokines were assessed in 83 patients with early sepsis and 41 hospital controls, and related to reactive hyperaemia-peripheral arterial tonometry, RH-PAT, a measure of endothelial NO bioavailability.ResultsPlasma Ang-2 was elevated in sepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organ failure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P < 0.0001). It correlated inversely with RH-PAT (r = -0.38, P < 0.0001) and positively with IL-6 (r = 0.57, P < 0.0001) and degree of organ failure (sequential organ function assessment score) (r = 0.58, P < 0.0001). The correlation of ang-2 with RH-PAT persisted after controlling for sepsis severity. In a longitudinal mixed-effects model, recovery of RH-PAT over time was associated with decline in ang-2.ConclusionsAng-2 is elevated in proportion to sepsis severity, and inversely correlated with NO-dependent microvascular reactivity. Impaired endothelial NO bioavailability may contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak. Agents that increase endothelial NO bioavailability or inhibit WPB exocytosis and/or Ang-2 activity may have therapeutic potential in sepsis.

Highlights

Angiopoietin-2, an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability
Plasma Ang-2 was elevated in sepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organ failure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P < 0.0001)
Impaired endothelial Nitric oxide (NO) bioavailability may contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak

Summary

Introduction

Angiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Nitric oxide (NO) inhibits WPB exocytosis, and bioavailability of endothelial NO is decreased in sepsis. Angiopoietin-2 (ang-2), an angiogenic peptide, activates endothelial cells and increases vascular inflammation. It functions as an autocrine mediator of the endothelium and is stored predominantly in endothelial cells [2]. 1-induced Tie-2 receptor autophosphorylation responsible for the maintenance of endothelial cell quiescence [3] This results in endothelial cells being sensitized to the effects of pro-inflammatory cytokines and vascular endothelial growth factor (VEGF), resulting in a loss of endothelial cell quiescence and an increase in vascular activation and inflammation. There are only two known inhibitors of WPB release: nitric oxide (NO) and hydrogen peroxide (H2O2), of which NO is thought to be the most important [14]

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