Endothelial Activation: The Ang/Tie Axis in Sepsis

Abstract

Sepsis, a dysregulated host response to infection that causes life-threatening organ dysfunction, is a highly heterogeneous syndrome with no specific treatment. Although sepsis can be caused by a wide variety of pathogenic organisms, endothelial dysfunction leading to vascular leak is a common mechanism of injury that contributes to the morbidity and mortality associated with the syndrome. Perturbations to the angiopoietin (Ang)/Tie2 axis cause endothelial cell activation and contribute to the pathogenesis of sepsis. In this review, we summarize how the Ang/Tie2 pathway is implicated in sepsis and describe its prognostic as well as therapeutic utility in life-threatening infections.

Plasma PTX3, MCP1 and Ang2 are early biomarkers to evaluate the severity of sepsis and septic shock

“…Vascular endothelial cells lining in the inner side of vascular system play a significant role in maintaining vascular homeostasis. In the early stage of sepsis, excessive release of pro‐inflammatory cytokines and the adhesion of leucocytes disrupt endothelial cell integrity and eventually lead to vascular leakage, disturbance of blood flow and sepsis‐induced organ failure . In severe infections and sepsis, persistent vascular damage and leakage can contribute to tissue hypoperfusion.…”

“…The endothelial-specific angiopoietin (Ang)-tyrosine kinase (Tie) system has been considered as an important mechanism in regulating endothelial activation of sepsis and as a possible determinant of injury severity. 18 Angiopoietin 1 (Ang1) is released by pericytes, and it enhances the stability of formed vessels by binding to its receptor Tie2 in endothelial cells. 19 Ang2 is stored in Weibel-Palade bodies in endothelial cells.…”

New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria

“…In a non-disease state, there is a higher concentration of circulating Ang-1 than Ang-2 promoting microvascular quiescence. During malaria infection, Ang-2 and vWF are released from Weibel-Palade bodies (WPB) within the endothelial cells, antagonizing Tie-2 activation and triggering a pro-coagulant and pro-inflammatory state, associated with microvascular activation and a risk of SM, reviewed in [79]. Hence, the ratios of Ang-1 and Ang-2 are indicative of endothelial dysregulation, where higher Ang-2 and lower Ang-1 levels indicate progression to severe and potential fatal disease [80].…”

“…This study showed that even after the initiation of microvascular leak as determined by Evan's blue dye extravasation into the brain parenchyma, agents such as BowAng1, can prevent further brain injury and death compared to artesunate alone. More therapeutic interventions targeting the Ang-1/Tie-2 axis are reviewed in [79]. Likewise, the heme axis is a potential intervention point that remains to be explored.…”

“…Circulating mediators of immune and endothelial activation (e.g. Ang-2, sTREM-1) measured at first clinical presentation have been shown to be accurate in risk stratifying not only in malaria patients (Figure 2), but for all cause febrile syndromes [79,80,88,137,138]. Although, large prospective studies will be required to prove clinical utility, incorporating these markers in rapid POC tests could permit risk stratification of fever syndromes in both low and high resource settings.…”