Angiopoietin-1 variant reduces LPS-induced microvascular dysfunction in a murine model of sepsis.

Abstract

INTRODUCTION:

Severe sepsis is characterised by intravascular or extravascular infection with microbial agents, systemic inflammation and microcirculatory dysfunction, leading to tissue damage, organ failure and death. The growth factor angiopoietin (Ang-1) has therapeutic potential but recombinant Ang-1 tends to aggregate and has a short half-life in vivo. This study aimed to investigate the acute effects of the more stable Ang-1 variant matrilin-1-angiopoietin-1 (MAT.Ang-1) on the function of the microcirculation in an experimental model of sepsis, and whether any protection by MAT-Ang-1 was associated with modulation of inflammatory cytokines, angiogenic factors or the endothelial nitric oxide synthase (eNOS)-Akt and vascular endothelial (VE)-cadherin pathways.

METHODS:

Aluminium window chambers were implanted into the dorsal skinfold of male C3H/HeN mice (7 to 10 weeks old) to expose the striated muscle microcirculation. Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg at 0 and 19 hours). MAT.Ang-1 was administered intravenously 20 hours after the onset of sepsis. Microcirculatory function was evaluated by intravital microscopy and Doppler fluximetry.

RESULTS:

Endotoxemia resulted in macromolecular leak, which was ameliorated by MAT.Ang-1 post-treatment. LPS induced a dramatic reduction in tissue perfusion, which was improved by MAT.Ang-1. Proteome profiler array analysis of skeletal muscle also demonstrated increased inflammatory and reduced angiogenic factors during endotoxemia. MAT.Ang-1 post-treatment reduced the level of IL-1β but did not significantly induce the expression of angiogenic factors. MAT.Ang-1 alone did not induce leak or increase angiogenic factors but did reduce vascular endothelial growth factor expression in controls.

CONCLUSION:

Administration of MAT.Ang-1 after the onset of sepsis protects the microcirculation from endotoxemia-induced vascular dysfunction through reducing inflammation but without pro-angiogenic actions, thus representing a novel, potential pharmacotherapeutic agent for the treatment of sepsis.

• Authors: Alessio Alfieri, Jay J Watson, Richard A Kammerer, Mohammed Tasab, Pavlos Progias, Kimberly Reeves, Nicola J Brown, Zoe L Brookes
• Journal: Critical care (London, England) (Crit Care) Vol. 16 Issue 5 Pg. R182 (Oct 04 2012) ISSN: 1466-609X [Electronic] England
• PMID: 23036162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-1
• Angpt1 protein, mouse
• Lipopolysaccharides

Topics

• Angiopoietin-1 (administration & dosage, genetics)
• Animals
• Disease Models, Animal
• Genetic Variation (genetics)
• Humans
• Lipopolysaccharides (toxicity)
• Male
• Mice
• Mice, Inbred C3H
• Microcirculation (drug effects, physiology)
• Random Allocation
• Sepsis (chemically induced, drug therapy, genetics)