The specificity of receptor binding by vascular endothelial growth factor-D is different in mouse and man

Human vascular endothelial growth factor-D (VEGF-D) binds and activates VEG FR-2 and VEGFR-3, receptors expressed on vascular and lymphatic endothelial cells. As VEGFR-2 signals for angiogenesis and VEGFR-3 is thought to signa l for lymphangiogenesis, it was proposed that VEGF-D stimulates growth of b lood vessels and lymphatic vessels into regions of embryos and tumors. Here we report the unexpected finding that mouse VEGF-D fails to bind mouse VEG FR-2 but binds and cross-links VEGFR-3 as demonstrated by biosensor analysi s with immobilized receptor domains and bioassays of VEGFR-2 and VEGFR-3 cr oss-linking. Mutation of amino acids in mouse VEGF-D to those in the human homologue indicated that residues important for the VEGFR-2 interaction are clustered at, or are near, the predicted receptor-binding surface. Coordin ated expression of VEGF-D and VEGFR-3 in mouse embryos was detected in the developing skin where the VEGF-D gene was expressed in a layer of cells ben eath the developing epidermis and VEGFR-3 was localized on a network of ves sels immediately beneath the VEGF-D-positive cells. This suggests that VEGF -D and VEGFR-3 may play a role in establishing vessels of the skin by a par acrine mechanism. Our study of receptor specificity suggests that VEGF-D ma y have different biological functions in mouse and man.