TWEAK induces angiogenesis and proliferation of endothelial cells

TWEAK is a recently described member of the Tumor Necrosis Factor (TNF) lig and family whose transcripts are present in a wide variety of human tissues (Chicheportiche, Y., Bourdon, P. R., Xu, H., Hsu Y. M., Scott, H., Hession , C., Garcia, I., and Browning, J. L. (1997) J. Biol. Chem. 272, 32401-3241 0). TWEAK is a weak inducer of apoptosis in transformed cells when administ ered with interferon-gamma or cycloheximide (Chicheportiche, Y., Bourdon, P . R., Xu, H., Hsu Y. M., Scott, H., Hession, C., Garcia, I,, and Browning, J. L. (1997) J. Biol. Chem. 272, 32401-32410; Masters, S. A., Sheridan, J. P., Pitti, R. M., Brush, A. G., and Ashkenazi, A. (1998) Curr. Biol. 8, 525 -528) and also promotes IL-8 secretion in cultured cells. We report here th at picomolar concentrations of recombinant soluble TWEAK induce proliferati on in a variety of normal human endothelial cells and in aortic smooth musc le cells and reduce culture requirements for serum and growth factors. Bloc king antibodies to Vascular Endothelial Growth Factor (VEGF) do not signifi cantly inhibit TWEAK-induced proliferation, indicating that TWEAK does not function indirectly through up-regulation of VEGF. Pellets containing TWEAK induce a strong angiogenic response when implanted in rat corneas, suggest ing a role for TWEAK in vasculature formation in vivo.