Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells

Normally, tissue factor (TF) is not expressed on the surface of endothelial cells, but its expression can be induced by vascular endothelial growth fa ctor (VEGF) and tumor necrosis factor (TNF)-alpha. However, the signaling p athway(s) affecting this induction is unknown. Using human umbilical vein e ndothelial cells, we found that inhibitors of guanine-cytosine-rich DNA bin ding protein and nuclear factor (NF)-kappaB suppressed VEGF- and TNF-alpha -induced expression and activity of TF. However, unexpectedly, phosphatidyl inositol (PI) 3'-kinase inhibitor enhanced the VEGF- and TNF-alpha -induced expression and activity of TF. Angiopoietin-1 (Ang1), a strong activator o f intracellular PI 3'-kinase/Akt, inhibited the induction of TF by VEGF and TNF-alpha, whereas Ang1 itself did not produce any significant effect on T F. Selective activation (or inactivation) of PI 3'-kinase/Akt by using aden oviral transfer reduced (or enhanced) TNF-alpha -induced expression of TF m RNA and protein, regardless of Ang1 treatment. From these results, we concl ude that Ang1 inhibits the up-regulation of TF expression, possibly through activation of PI 3'-kinase/Akt in endothelial cells. Ang1 may be useful as an inhibitor of VEGF- and TNF-alpha -induced coagulation, inflammation, an d cancer progression.