title: Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity.
abstract: BACKGROUND
  Angiopoietin-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.
  
  
  METHODS
  Plasma 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.
  
  
  RESULTS
  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). 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.
  
  
  CONCLUSIONS
  Ang-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.
authors.affiliation: International Health Division, Menzies School of Health Research and Charles Darwin University, Ellengowan Drive, Casuarina, Darwin, NT 0810, Australia. Joshua.Davis@menzies.edu.au
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Davis
authors.forename: Tsin W
authors.initials: TW
authors.lastname: Yeo
authors.forename: Kim A
authors.initials: KA
authors.lastname: Piera
authors.forename: Tonia
authors.initials: T
authors.lastname: Woodberry
authors.forename: David S
authors.initials: DS
authors.lastname: Celermajer
authors.forename: Dianne P
authors.initials: DP
authors.lastname: Stephens
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D001315:Australia; D002199:Capillary Permeability / Q000276:immunology; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D011446:Prospective Studies; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D042702:Angiopoietin-2; D009569:Nitric Oxide