Vascular endothelial 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 cystine knot structure (1-3). 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) (1, 2). Proteolytic processing of the 354 aa 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 (4-6). Mature human VEGF-D shares 94%, 95%, 99%, 97% and 93% aa identity with mouse, rat, equine, canine and bovine VEGF-D, respectively (4, 5). It is expressed in adult lung, heart, muscle, and small intestine, and is most abundantly expressed in fetal lungs and skin (1-4). 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 (7). Processed human VEGF-D is also a ligand for VEGF R2, also called Flk-1 or KDR (7). VEGF R3 is strongly expressed in lymphatic endothelial cells and is essential for regulation of the growth and differentiation of lymphatic endothelium (1, 2). 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 (8-10). Both promote tumor lymphangiogenesis (11). 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 (12, 13).
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