VEGF is a potent growth factor that promotes both angiogenesis and vascular permeability (1-3). It acts on endothelial cells by signaling primarily through two VEGF receptors, VEGF R1 (also called Flt-1) and VEGF R2 (Flk-1/KDR). VEGF's main responsibility is to induce blood vessel formation during development and following tissue injury, and to bypass blocked blood vessels. During embryogenesis, VEGF is required for proliferation, migration, and survival of endothelial cells (3, 4). In addition, VEGF also plays a role in several other physiological processes such as hematopoiesis, bone formation, wound healing, and neuronal development. Pathologically, VEGF is involved in tumor angiogenesis and vascular leakage (6, 7), and it has been implicated as a major player in many different cancers, both solid tumors and hematopoietic malignancies. Circulating VEGF levels correlate with disease activity in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus (8). VEGF expression is induced by hypoxia and cytokines such as IL-1, IL-6, IL-8, oncostatin M and TNF-alpha (3, 4, 9).
Structurally, VEGF is a member of the PDGF family that is characterized by the presence of eight conserved cysteine residues and a cystine knot structure (4). Humans express multiple alternately spliced isoforms resulting in polypeptides that are 121, 145, 165, 183, 189, and 206 amino acids (aa) in length (4). Each isoform is named based on its length. VEGF 165 appears to be the most abundant and potent isoform, followed by VEGF 121 and VEGF 189 (3, 4). Isoforms other than VEGF 121 contain basic heparin-binding regions and are not freely diffusible (4). Human VEGF165 shares 88% aa sequence identity with corresponding regions of mouse and rat, 96% with porcine, 95% with canine, and 93% with feline, equine and bovine VEGF, respectively. VEGF signals by binding to the type I transmembrane receptor tyrosine kinases VEGF R1 (also called Flt-1) and VEGF R2 (Flk-1/KDR) on endothelial cells (4). Although VEGF affinity is highest for binding to VEGF R1, VEGF R2 appears to be the primary mediator of VEGF angiogenic activity (3, 4). VEGF 165 also binds the semaphorin receptor, Neuropilin-1 and promotes complex formation with VEGF R2 (5).
