Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and invitro

Exponential tumor growth is angiogenesis-dependent. Vascular endothelial gr owth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent ang iogenic inducers that act synergistically in vivo and in vitro. We assessed the effect of specific inhibitors of VEGF receptor (VEGFR)-2 tyrosine kina se activity in in vivo and in vitro models of VEGF- and bFGF-induced angiog enesis. In an implant mouse model of angiogenesis, VEGFR-2 inhibitors compl etely blocked angiogenesis induced by VEGF, and, surprisingly, also inhibit ed the effect of bFGF to various extents. In vitro, VEGF- and bFGF-induced bovine microvascular and aortic endothelial (BME and BAE) cell collagen gel invasion could be blocked by the VEGFR-2 inhibitors by 100 and similar to 90%, respectively. Similar results were obtained with VEGFR-1-IgG and VEGFR -3-IgG fusion proteins and with VEGFR-2 blocking antibodies. Both BME and B AE cells produce VEGF and VEGF-C, which is not modulated by bFGF. Thus, the unexpected inhibition of bFGF-induced angiogenesis by VEGFR-2 antagonists reveals a requirement for endogenous VEGF and VEGF-C in this process. These findings broaden the spectrum of mediators of angiogenesis that can be inh ibited by VEGFR-2 antagonists and highlight the importance of these compoun ds as agents for inhibiting tumor growth sustained by both VEGF and bFGF.