Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivityReport as inadecuate

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Critical Care

, 14:R89

First Online: 18 May 2010Received: 20 November 2009Revised: 02 February 2010Accepted: 18 May 2010


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.


APACHEAcute Physiology and Chronic Health Evaluation

CBAcytokine bead array

CIconfidence interval

ELISAenzyme-linked immunosorbent assay

H2O2hydrogen peroxide

ICAM-1intra-cellular adhesion molecule-1


IQRinterquartile range

NSFN-ethyl-malemide sensitive factor

NOnitric oxide

RH-PATreactive hyperemia peripheral arterial tonometry

SIRSsystemic inflammatory response syndrome

SOFASequential Organ Failure Assessment

TNFαtumour necrosis factor α

VEGFvascular endothelial growth factor

vWFvon Willebrand factor

WPBWeibel Palade bodies.

Electronic supplementary materialThe online version of this article doi:10.1186-cc9020 contains supplementary material, which is available to authorized users.

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Author: Joshua S Davis - Tsin W Yeo - Kim A Piera - Tonia Woodberry - David S Celermajer - Dianne P Stephens - Nicholas M Ans


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