Direct actions of angiopoietin-1 on human endothelium: Evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors

Angiopoietin-1 (Ang-1) is a recently described angiogenic protein that activates the endothelial Tie 2 receptor. Disruption of the Ang-1 gene shows that it has an indispensable role in blood vessel development, but it is not clear what specific effects, if any, Ang-1 has on endothelial cell (EC) phenotypes. Here, we show that Ang-1 dose-dependently stabilizes HUVEC network organization for up to 48 hours; this action of Ang-1 is dependent on Tie-2 receptor activation, because a soluble form of the Tie2-, but not the Tie1-receptor, completely blocks the effects of Ang-1. Moreover, we show that Ang-1 potentiates the actions of other angiogenic growth factors. Ang-1 markedly increases the survival of vascular networks (up to 96 hours) exposed to either vascular endothelial growth factor or endothelial cell growth supplement, a form of acidic fibroblast growth factor. In addition, Ang-1 prevents apoptotic death in HUVEC triggered by withdrawal of endothelial cell growth supplement. Collectively, these data are consistent with the idea that Ang-1 directly acts on human EC and interacts with other angiogenic molecules to stabilize vascular structures by promoting the survival of differentiated ECs.