Vascular permeability factor/vascular endothelial growth factor and its receptors: Evolving paradigms in vascular biology and cell signaling

VASCULAR ENDOTHELIAL GROWTH FACTORS Background and Discovery The pioneering observations of Dvorak and his group first showed that tumor ascites fluids from guinea pigs, hamsters, and mice contained an activity that rapidly increased micro-vascular permeability. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor – the guinea pig line 10 hepatocarcinoma – was a 34,000-to 42,000-dalton protein that was distinct from other known permeability factors (1).The vascular permeability factor (VPF) was also secreted by five human tumor cell lines and could be eluted from immobilized heparin. Two tumorigenic (in nude mice) human cell lines were found to secrete at least 14-fold more VPF than their directly matched, nontumorigenic counterparts, suggesting that this factor was important for tumor growth (2). Later Ferrara and colleagues, and others, isolated a heparin-binding growth factor from the conditioned media of bovine pituitary follicular cells (FCs) and described it as vascular endothelial growth factor (VEGF). This factor was specific for vascular endothelial cells (ECs) and was able to induce angiogenesis in vivo. Complementary DNA (cDNA) clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, and it was subsequently recognized that VPF and VEGF were encoded by a single gene (3–7). Gene and Splice Variants The human VEGF gene, located on the short arm of chromosome 6, is comprised of eight exons (8) and gives rise to five isoforms containing 121, 145, 165, 189, and 206 amino acids, respectively, that are produced as a result of alternate splicing (9–11). The full transcript encodes a 189-amino acid isoform.