Chimeric VEGF-E(NZ7)/PlGF promotes angiogenesis via VEGFR-2 without significant enhancement of vascular permeability and inflammation.

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.