The role of Ang/Tie signaling in lymphangiogenesis.

The angiopoietin/Tie system plays a key role in remodeling and maturation of blood vessels as well as lymphatic vessels. The angiopoietin family includes four ligands (Ang-1, Ang-2 and Ang-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). The best characterized angiopoietins are Ang-1 and Ang-2. Ang-1 acts as an obligate agonist of the Tie2 receptor. Binding of Ang-1 to Tie2 induces its autophosphorylation and promotes vascular stability and integrity. Ang-1 induces lymphatic vessel enlargement, sprouting and proliferation in a VEGFR-3-dependent manner. In contrast, whether Ang-2 is agonistic or antagonistic is dependent on dose and context. Ang-2 modulates angiogenesis in a cooperative manner with another important angiogenic factor, vascular endothelial growth factor A. In the presence of VEGF-A, Ang-2 promotes vascular sprouting. When in the absence of VEGF-A, Ang-2 induces vascular regression. However, genetic studies have revealed that Ang-2-deficient mice exhibit more severe defects in the lymphatic vasculature than in blood vessels. Ang-2 seems to be involved in the remodeling and stabilization of lymphatic vessels. Although the Ang/Tie system is essential for blood and lymphatic vessel remodeling and maturation, defining its precise role in blood and lymphatic development has been a major challenge. This review provides an update on our current understanding of the angiopoietin/Tie system in lymphangiogenesis.