ANGIOGENESIS Endostatin's Signaling Network

Endostatin is an endogenous antiangiogenic peptide that inhibits endothelial cell proliferation, migration, and tube formation. Abdollahi et al. performed cDNA and antibody microarray analysis along with selected Western blotting and immunocytochemistry to show that endostatin regulates multiple pathways in human dermal microvascular endothelial cells that converge to produce the antiangiogenic effect. At the level of gene expression, endostatin regulated ~12% of the genome, with genes associated with promotion of angiogenesis generally being down-regulated and genes associated with stress responses being up-regulated. The antibody arrays showed that for many of the pathways, the phosphorylation status of individual proteins was altered by endostatin treatment. Eight signaling cascades that were down-regulated by endostatin treatment were investigated in more detail: Id signaling and activator protein 1 signaling (cell proliferation), hypoxia inducible factor 1α signaling (low oxygen and metabolic adaptation), ephrin and tumor necrosis factor α signaling (cell migration), nuclear factor B (proliferation and antiapoptosis), signal transducer and activator of transcription signaling (regulator of proliferation and migration), Ets (migration and antiapoptosis), coagulation cascades, and adhesion molecules pathways. These results identify several new pathways regulated by endostatin and present a picture of a complex network of responses that contribute to the antiangiogenic activity of a single ligand.

A, Abdollahi, P. Hahnfeldt, C. Maercker, H.-J. Gröne, J. Debus, W. Ansorge, J. Folkman, L. Hlatky, P. E. Huber, Endostatin's antiangiogenic signaling network. Mol. Cell 13, 649-663 (2004). [Online Journal]