Chemotactic Properties of Angiopoietin-1 and -2, Ligands for the Endothelial-specific Receptor Tyrosine Kinase Tie2

Angiopoietin-1 and its putative natural antagonist, angiopoietin-2, were recently isolated, and the critical role of angiopoietin-1 in embryogenic angiogenesis was demonstrated by targeted gene disruption. Specific biological effects of angiopoietin-1, however, have yet to be defined. In this study we demonstrate that angiopoietin-1, but not angiopoietin-2, is chemotactic for endothelial cells. In contrast, angiopoietin-1 as well as angiopoietin-2 exhibit no proliferative effect on endothelial cells. Excess soluble Tie2, but not Tie1 receptor, abolish the chemotactic response of endothelial cells toward angiopoietin-1. Angiopoietin-2 dose-dependently blocks directed migration toward angiopoietin-1, consistent with the role of angiopoietin-2 as a naturally occurring inhibitor of angiopoietin-1. Fibroblasts stably transfected with Tie2 receptor exhibit chemotactic responses for both angiopoietin-1 and angiopoietin-2. Fibroblasts stably expressing a transfected chimeric receptor consisting of the ectodomain of TrkC fused to the cytoplasmic domain of Tie2 also exhibit a chemotactic response to neurotrophin 3 (NT-3), a specific ligand for TrkC. Endothelial cells are shown to express angiopoietin-2 mRNA and protein, indicating the potential for autocrine activation of angiopoietin/Tie2. Finally, the demonstration that Tie2 as well as angiopoietin-1 are expressed in normal human arteries and veins suggests that the role of angiopoietin/Tie2 may extend beyond embryonic angiogenesis to maintaining integrity of the adult vasculature.