Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Abstract

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Tie2 | endothelium | infection | angiopoietin | permeability

Tie2 protects the vasculature against thrombus formation in systemic inflammation

“…Levels of phosphorylated (active) Tie2 were significantly decreased in endotoxemic mice at the early 3-hour time point compared with saline controls (Figure 3, G and H). The temporal profile of the Angpt-1/ Angpt-2 ratio in circulation (Supplemental Figure 2A) suggested that an early decline in Angpt-1 ( Figure 3I) contributed to reduced Tie2 signaling, which in turn, derepressed Angpt-2 ( Figure 3J), consistent with prior studies (19,(41)(42)(43)(44). To assess whether the loss of vascular quiescence indicated by reduced Tie2 signaling was more broadly manifest, we analyzed a panel of endothelial activation markers in plasma collected at 3 hours after LPS; PAI-1, von Willebrand factor (VWF), and soluble forms of endothelial adhesion molecules (sE-selectin and sVCAM-1) were all elevated at the early 3-hour time point (Supplemental Figure 2, B-E).…”

“…As dysregulation of the Angpt/Tie2 pathway was associated with a prothrombotic state, we next studied microvascular thrombus formation in Tie2 +/-mice. Heterozygous mice are indistinguishable from wild-type (WT) littermates at baseline, but exhibit increased susceptibility to inflammation and infections (19,37,45). Unexpectedly, partial Tie2 deficiency alone was sufficient to enhance fibrin deposition independent of LPS ( Figure 5, A-E).…”

“…Whereas the clinical criteria for DIC relate solely to platelets and coagulation parameters, network analysis of the proteomics strongly implicated the endothelium, including alterations in the endothelial regulatory angiopoietin-1 (Angpt-1)/Tie2 signaling axis. Tie2 is a receptor that is highly enriched in the endothelium and actively signals vascular quiescence (19)(20)(21)(22). Tie2 is stimulated by Angpt-1, a protein secreted by periendothelial cells and platelets.…”

Tie1 controls angiopoietin function in vascular remodeling and inflammation

“…Reduced Ang2 gene dosage (31), ANG2 blocking antibodies (32), and ectopic ANG1 reduce sepsis-induced vascular leak and lung injury in mice (33). In comparison, mice expressing reduced Tie2 levels are more susceptible to LPS-induced endotoxemia (34,35). ANG2 inhibition also reduces the harmful inflammation associated with cardiac transplant rejection (36) and improves endothelial-pericyte interactions in diabetic retinopathy (37).…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…97 At present, Ang-2/Ang-1 ratios remain an excellent marker for severe disease, but whether this pathway contributes critically to human cerebral malaria or acute lung injury as seen in sepsis remains unclear. 98 Host-derived products released at the time of red blood cell rupture such as free heme and its parent compound, hemoglobin, have also been implicated in pediatric 99 and adult 100 severe malaria as well as in endothelial dysfunction in malaria. 101 Heme is known to disrupt endothelial barriers directly through induction of free radical generation and mitochondrial reactive oxygen species signaling in endothelial cells.…”