Objective: Vascular endothelial growth factor (VEGF) plays critical roles in the regulation of angiogenesis and lymphangiogenesis. However, tissue edema, hemorrhage, and inflammation occur when VEGF-A is used for angiogenic therapy. To design a novel angiogenic factor without severe side effects, we examined the biological function of chimeric VEGF-E(NZ7)/placental growth factor (PlGF), which is composed of Orf-Virus(NZ7)-derived VEGF-E(NZ7) and human PlGF1, in a transgenic (Tg) mouse model.
Methods and results: A strong angiogenic response was observed in both VEGF-E(NZ7)/PlGF and VEGF-A165 Tg mice. Notably, the vascular leakage of VEGF-E(NZ7)/PlGF-induced blood vessels was 4-fold lower than that of VEGF-A165-induced blood vessels. Furthermore, the monocyte/macrophage recruitment in the skin of VEGF-E(NZ7)/PlGF Tg mice was approximately 8-fold decreased compared with that of VEGF-A165 Tg mice. In addition, the lymphatic vessels in VEGF-E(NZ7)/PlGF Tg mice were structurally normal, whereas they were markedly dilated in VEGF-A165 Tg mice, possibly because of the high vascular leakage. Receptor binding assay demonstrated that VEGF-E(NZ7)/PlGF was the ligand only activating VEGF receptor (VEGFR)-2.
Conclusions: These results indicated that neither the hyperpermeability in response to simultaneous stimulation of VEGFR-1 and VEGFR-2 nor VEGFR-1-mediated severe inflammation was associated with VEGF-E(NZ7)/PlGF-induced angiogenesis. The unique receptor binding property may shed light on VEGF-E(NZ7)/PlGF as a novel candidate for therapeutic angiogenesis.