The endothelial Tie1 receptor is
ligand-less, but interacts with the
Tie2 receptor for
angiopoietins (Angpt). Angpt2 is expressed in
tumor blood vessels, and its blockade inhibits
tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits
tumor angiogenesis and growth by decreasing endothelial cell survival in
tumor vessels, without affecting normal vasculature. Treatment with
VEGF or
VEGFR-2 blocking antibodies similarly reduced
tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and
VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of
tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted
retinal hypervasularization. Moreover, substantial additive inhibition of the
retinal vascular front migration was observed when Angpt2
blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates
tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by
VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic
therapy.