Role of Ang1 and its interaction with VEGF-A in astrocytomas.

Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.