The receptor tyrosine kinase Tie-1 is expressed predominantly in endothelial cells where it physically associates with the related receptor Tie-2. Positive signalling through Tie-2 is associated with microvessel stability and suppression of this signal is thought to be required for vascular endothelial growth factor (VEGF)-induced microvessel remodelling or growth. Here we examine the effects of VEGF on Tie-1 and the Tie-2:Tie-1 complex. We show that VEGF induces generation of the Tie-1 endodomain and loss of the full-length receptor. The effects of VEGF on endodomain formation are not suppressed by inhibitors of protein kinase C and do not involve the nitric oxide signalling pathway. Tyrosine kinase inhibitors, in contrast, do abolish endodomain generation in response to the endothelial growth factor. VEGF stimulation of cells does not cause dissociation of the Tie-2:Tie-1 complex; rather the complex is converted to a form comprising the full-length-Tie-2 and Tie-1 endodomain. VEGF can therefore switch the Tie-2:Tie-1 complex between two different forms in endothelial cells. The ability of VEGF to modulate Tie-1 and the Tie-2:Tie-1 complex provides a mechanism whereby this initiator of vessel growth and remodelling can directly modulate receptors involved in vessel stabilization. Such cross-talk is likely to be important in the coordinate control of blood vessel formation during development and in postnatal angiogenesis.