Figure 5.

Endothelial Angpt/Tie2 signalling is compromised in sepsis. A key regulator of endothelial homeostasis – Tie2 – is heavily modulated in sepsis, which can result in endothelial dysfunction. Angpt1 and APC serve as agonists for Tie2, whereas Angpt2 competitively binds to Tie2, preventing its activation. Angpt1 and Angpt2 can also bind to TM, hereby inhibiting EPCR/TM/thrombin-dependent conversion of PC to APC. Tie2 activity is further modulated through association with Tie1, which lowers the activation threshold of Tie2 to promote its activation, and VE-PTP, which decreases Tie2 activation status through dephosphorylation. TNFα/TNRF1 promotes cleavage of the extracellular domain of Tie2 via MMP14. Upon activation, Tie2 exerts an anti-inflammatory effect by activating ABIN-2, which prevents nuclear translocation of NF-κB. In addition, Tie2 activates Ras/ERK/SK1 and PI3K/AKT. Finally, Tie2 has a protective effect on endothelial barrier function through PI3K-dependent activation of Rac1, and RhoA-dependent activation of mDia. ABIN-2, A20-binding inhibitor of NF-κB activation-2; AKT, protein kinase B; Angpt1, angiopoietin-1; Angpt2, angiopoietin-2; APC, activated protein C; ERK, extracellular signal-regulated kinase; mDia, mammalian Diaphanous-related formin Dia; MMP14, matrix metalloproteinase-14; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; Ras, Ras protein subfamily; RhoA, Ras homolog gene family, member A; SK1, sphingosine kinase 1; T, thrombin; Tie1, tunica intima endothelial kinase 1; Tie2, tunica intima endothelial kinase 2; TM, thrombomodulin; TNFR1, tumor necrosis factor alpha receptor 1; TNFα, tumor necrosis factor alpha; VE-PTP, vascular endothelial protein tyrosine phosphatase.