Mending Leaky Blood Vessels: The Angiopoietin-Tie2 Pathway in Sepsis

Abstract

Sepsis is a systemic inflammatory response to infection. A common end-feature, these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypoperfusion, coagulopathy, immune dysregulation, and mitochondrial dysfunction. Microvascular dysfunction critically contributes to the morbidity and mortality of this disease. The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt-1, -2, and -3/4). The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial barrier function and the leakage and vascular inflammation that develop in response to pathogens and cytokines. Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease.

Pulmonary Surfactant Protein A Is Expressed in Mouse Retina by Muller Cells and Impacts Neovascularization in Oxygen-Induced Retinopathy

“…In the context of the developing blood vessels, this may alter the expression of pro-angiogenic signaling molecules such as VEGF as well as molecules that maintain blood vessel integrity (e.g., angiopoeitin-1/2). 52 The in vivo expression of SP-A in the mouse retina after intravitreal injection of TLR-2 and TLR-4 ligands demonstrates that inflammatory pathways induced by common bacterial pathogens (e.g., LPS-mediated TLR-4 activation) led to an increase in retinal SP-A levels, Although our data are from adult mice, several studies have shown an increased risk of ROP in the face of maternal chorioamnionitis with postnatal infections and sepsis. 21,53 Our in vivo studies demonstrated that SP-A expression was more pronounced for LPS-mediated TLR-4 activation, although Pam3Cys-mediated TLR-2 activation was found to occur earlier (12 hours vs. 6 hours).…”

The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation

“…Although some studies suggest a protective role of Angpt-2 in the context of infection, the majority of the literature supports the concept that Angpt-2 is deleterious in sepsis (reviewed in 55 ). Recently, Western analysis of lung homogenates from septic mice has shown that Angpt-2 siRNA-knockdown restores Tie2 phosphorylation, providing in vivo evidence that the induction of Angpt-2 in sepsis leads to Tie2 deactivation and that Angpt-2 worsens outcomes in sepsis.…”

Therapeutic strategies in pneumonia: going beyond antibiotics

“…Ang-1 and -2 are important regulators of angiogenesis, inflammation and vascular permeability [78,79]. Binding of constitutively expressed Ang-1 to Tie2 induces endothelial quiescence, integrity and barrier stabilisation.…”