Tie-1: A potential target for anti-angiogenesis therapy.

The tyrosine kinase system angiopoietin (Ang)/Tie interacts with vascular endothelial growth factor pathway and regulates vessel quiescence in adults as well as later steps of the angiogenic cascade related to vessel maturation. Since all Angs are able to bind to Tie-2 but none binds to Tie-1, the function of Tie-2 and its ligands have captured attention. However, emerging evidence indicates unique roles of the orphan receptor Tie-1 in angiogenesis under physiological and pathological conditions. It is required for maintaining vascular endothelial cell integrity and survival during murine embryo development and in adult and may be involved in modulating differentiation of hematopoietic cells in adult. Tie-1 exhibits poor tyrosine kinase activity and signals via forming heterodimers with Tie-2, inhibiting Tie-2 signaling mediated by Angs. This inhibition can be relieved by Tie-1 ectodomain cleavage mediated by tumor- and inflammatory-related factors, which causes destabilization of vessels and initiates vessel remodeling. Up-regulated Tie-1 expression has been found not only in some leukemia cells and tumor related endothelial cells but also in cytoplasm of carcinoma cells of a variety of human solid tumors, which is associated with tumor progression. In addition, it has pro-inflammatory functions in endothelial cells and is involved in some inflammatory diseases associated with angiogenesis. Recent research indicated that Tie-1 gene ablation exhibited significant effects on tumor blood- and lymph-angiogenesis and improved anti-Ang therapy, suggesting Tie-1 may be a potential target for tumor anti-angiogenesis treatment.

The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway.

The angiopoietin-Tie signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development. Although the basic functioning of the pathway is understood, many uncertainties remain about the role of certain members of the pathway, particularly angiopoietin-2 (Ang2), in pathological vascular remodeling and angiogenesis. We summarize the components of the angiopoietin-Tie pathway and then focus on studies that highlight the role of Ang2 in disease settings, including cancer and inflammation. The expression of Ang2 is elevated in many cancers and types of inflammation, which prompted the development of specific reagents to block its interaction with the Tie2 receptor. The application of these reagents in preclinical models of inflammation and cancer has begun to elucidate the role of Ang2 in vascular remodeling and disease pathogenesis and has led to emerging clinical tests of Ang2 inhibitors.

Suppression of Tie-1 in endothelial cells in vitro induces a change in the genome-wide expression profile reflecting an inflammatory function.

Tie-1 is an endothelial specific receptor tyrosine kinase that is upregulated in diseases such as atherosclerosis and rheumatoid arthritis. We recently demonstrated that Tie-1 induced a proinflammatory response when overexpressed in endothelial cells. Here, we used a complementary approach and suppressed endogenous Tie-1 expression in endothelial cells to examine its function by microarray analysis. Tie-1 appeared to govern expression of many genes involved in inflammation. Expression knockdown of Tie-1 significantly reduced endothelial conditioned medium ability to stimulate MCP-1 production in U937 cells. Collectively, our results support the notion that Tie-1 has an inflammatory function in endothelial cells.

Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis.

Angiopoietin-1 (Ang1) has key roles in development and maintenance of the vascular system. The ligand is a potent inhibitor of vascular leakage and suppresses endothelial apoptosis and vessel regression. Ang1 was originally identified as a ligand for the receptor tyrosine kinase Tie2. Recently however Ang1 has also been found to activate the related tyrosine kinase Tie1. The contribution of Tie1 to mediating the effects of Ang1 on endothelial function is not known. In this study we used an siRNA approach to investigate the relative importance of Tie1 and Tie2 in transducing the effects of Ang1 on monolayer permeability and induction of apoptosis in human endothelial cells. siRNA directed against either Tie1 or Tie2 suppressed expression of each respective receptor by more than 90%. Ang1 inhibited endothelial monolayer permeability and this effect was prevented by suppression of Tie2 expression. In contrast, Ang1 inhibition of permeability was not affected by suppression of Tie1 expression. The ability of Ang1 to inhibit induction of apoptosis in response to serum deprivation was completely blocked by suppression of Tie2 expression, but not diminished by suppression of Tie1 expression. Taken together these data demonstrate that Tie2 mediates the inhibitory effects of Ang1 on endothelial permeability and apoptosis. The data also demonstrates that Tie1 does not transduce anti-apoptotic or anti-permeability effects of Ang1 in endothelial cells.