Expression and hypoxic regulation of angiopoietins in human astrocytomas

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angio genesis and edema in human astrocytomas by its interaction with cognate end othelial-specific receptors (VEGFR1/R2). Tie1 and Tie2/Tek are more recentl y identified endothelial-specific receptors, with angiopoietins being ligan ds for the latter. These angiogenic factors and receptors are crucial for t he maturation of the vascular system, but their role in tumor angiogenesis, particularly in astrocytomas, is unknown. In this study, we demonstrate th at the angiopoietin family member Ang1 is expressed by some of the astrocyt oma cell lines. In contrast to VEGF, Ang1 is down regulated by hypoxia. Ang 2 was not overexpressed. Expression profiles of low-grade astrocytoma speci mens were similar to those of normal brain, with low levels of Ang1, Ang2, and VEGF expression. Glioblastoma multiforme expressed higher levels of Ang 1, but not to the same degree as pseudopalisading astrocytoma cells around necrotic and hypoxic zones expressed VEGF, as shown in previous studies. An g2 expression in the highly proliferative tumor vascular endothelium was al so increased, as was phosphorylated Tie2/Tek. The expression profile of the se angiogenic factors and their endothelial cell receptors in human gliobla stomas multiforme was similar to that in a transgenic mouse model of gliobl astoma multiforme. These data suggest that both VEGF and angiopoietins are involved in regulating tumor angiogenesis in human astrocytomas.