THE ROLE OF ANG/TIE SIGNALING IN LYMPHANGIOGENESIS

Abstract

The angiopoietin/Tie system plays a keyrole in remodeling and maturation of bloodvessels as well as lymphatic vessels. The angiopoietinfamily includes four ligands (Ang-1,Ang-2 and Ang-3/4) and two correspondingtyrosine kinase receptors (Tie1 and Tie2). Thebest characterized angiopoietins are Ang-1and Ang-2. Ang-1 acts as an obligate agonistof the Tie2 receptor. Binding of Ang-1 to Tie2induces its autophosphorylation and promotesvascular stability and integrity. Ang-1 induceslymphatic vessel enlargement, sprouting andproliferation in a VEGFR-3-dependentmanner. In contrast, whether Ang-2 isagonistic or antagonistic is dependent on doseand context. Ang-2 modulates angiogenesis ina cooperative manner with another importantangiogenic factor, vascular endothelial growthfactor A. In the presence of VEGF-A, Ang-2promotes vascular sprouting. When in theabsence of VEGF-A, Ang-2 induces vascularregression. However, genetic studies haverevealed that Ang-2-deficient mice exhibitmore severe defects in the lymphatic vasculaturethan in blood vessels. Ang-2 seems to beinvolved in the remodeling and stabilizationof lymphatic vessels. Although the Ang/Tiesystem is essential for blood and lymphaticvessel remodeling and maturation, defining itsprecise role in blood and lymphatic developmenthas been a major challenge. This reviewprovides an update on our current understandingof the angiopoietin/Tie system inlymphangiogenesis.