Vascular endothelia growth factor D (VEGF-D), also known as c-fos-induced growth factor (FIGF), is a secreted glycoprotein of the VEGF/PDGF family. VEGFs regulate angiogenesis and lymphangiogenesis during development and tumor growth, and are characterized by eight conserved cysteine residues that form a cysteine-knot structure . VEGF-C and VEGF-D, which share 23% amino acid (aa) sequence identity, are uniquely expressed as preproproteins that contain long N- and C-terminal propeptide extensions around the VEGF homology domain (VHD) . Proteolytic processing of either 358 aa or 326 aa splice forms of mouse VEGF-D preproprotein creates a secreted proprotein. Further processing by extracellular serine proteases, such as plasmin or furin-like proprotein convertases, forms mature VEGF-D consisting of non-covalently linked 42 kDa homodimers of the 117 aa VHD . Mature mouse VEGF-D shares 94%, 99%, 93%, 91% and 89% aa identity with the VHD of human, rat, equine, canine and bovine VEGF-D, respectively. It is expressed in adult lung, heart, muscle, and small intestine, and is most abundantly expressed in fetal lungs and skin . Mouse and human VEGF-D are ligands for VEGF receptor 3 (VEGF-R3, also called Flt-4) that are active across species and show enhanced affinity when processed . Unlike human VEGF-D, which is also a ligand for VEGF-R2 (also called Flk-1 or KDR), mouse VEGF-D does not bind to VEGF-R2 . VEGF-R3 is strongly expressed in lymphatic endothelial cells and is essential for regulation of the growth and differentiation of lymphatic endothelium . While VEGF-C is the critical ligand for VEGF-R3 during embryonic lymphatic development, VEGF-D is most active in neonatal lymphatic maturation and bone growth . Both promote tumor lymphangiogenesis . Consonant with their activity on VEGF receptors, binding of VEGF-C and VEGF-D to neuropilins contributes to VEGF-R3 signaling in lymphangiogenesis, while binding to integrin alpha 9 beta 1 mediates endothelial cell adhesion and migration .
