Vascular Endothelial Growth Factors (VEGFs) are 40-45KDa homodimers that belong to the cystine-knot platelet-derived growth factor (PDGF) family. The VEGF family has five subclasses VEGF-A, VEGF-B, VEGF-C, VEGF-D and PIGF (Placentaderived Growth Factor). The VEGF family of proteins represents a series of six ligands and three receptors along with co-receptors. Within the family of ligands the most broadly discussed is called VEGF, VEGF-A or historically vascular permeability factor (VPF), this 23kDa protein exists mainly in a 46kDa homodimeric state and is present in as many as six isoforms within human cells.
Acting as one of the key pro-angiogenic growth factors in the angiogenic switch, VEGF is a secreted mitogen that has the ability to impose great implications on the tissues expressing it. The signaling cascades that are initiated by the presence of VEGF have been extensively investigated and are known to lead to angiogenesis, vasopermeability, proliferation, survival and gene ex
In 1983 this growth factor was initially described by the Senger laboratory with respect to its role in inducing permeability in endothelial cells. Literature on the molecule coined VEGF began in 1989 and focused on its mitogenic characteristics and its ability to induce angiogenesis. Further work by the Senger laboratory in 1991 using cDNA sequencing was able to demonstrate that these two molecules were in fact the same.
Combining the information known for VEGF and VPF lead to the broader appreciation of VEGF-A as a significant participant in endothelial cell migration, mitosis, permeability, blood vessel lumen generation and as a vasodilator. In the last two decades another important characteristic of VEGF has been investigated and has lent support to its utilization as a target for therapeutics. Many studies have shown that VEGF can act as a survival factor in some cell lines, at various stages of development.
Studies have demonstrated the role of VEGF in stimulating survival pathways in other tissues such as breast cancer cells, prostate cancer cells and ovarian granulosa cells. The pleiotropic effects of VEGF make it an attractive target for cancer therapy as its inactivation will lead to both an inhibition of angiogenesis, reducing nutrient delivery to tumors and will also downregulate the stimulation of VEGF survival cascades.
A single gene coding sequence for VEGF-A is located on chromosome 6p21.3 in humans and resulting transcripts exhibit variable exon splicing to create isoforms 121, 145, 165, 183, 189 and 206a.a. in length. VEGF secretion is required for signaling between surrounding cells, thus requiring molecule solubility, as well as feedback regulation on the host cell. Feedback regulation can be more effectively accomplished by a less soluble isoform that as a result remains closely associated with the extracellular matrix. In the placenta although all of the VEGF isoforms were present less soluble, larger variants exhibited a much decreased copy number of mRNA transcripts over the more soluble forms.
The remaining members of the VEGF ligand family are collectively referred to as the VEGF-related proteins and as such all demonstrate variable degrees of homology to VEGF-A. This group includes the protein known as placental growth factor (P1GF) as well as VEGF-B, VEGF-C, VEGF-D and VEGF-E. Each of these proteins is expressed in a tissue specific manner with P1GF and VEGF-B occurring in embryonic angiogenesis and vasculogenesis, VEGF-C acting in lymphangiogenesis and VEGF-D acting in lung development. VEGF-E is a special case which has been observed in viruses and is presumed to be the result of genetic drift from a viral host. There is one more recently described form of VEGF (VEGF-F) which was isolated from snake venom and is composed of two VEGF-related proteins as well as exhibiting specificity for VEGFR-2 via its C-terminus heparin binding domain.
Each of the VEGF ligands interact with one or a combination of the three VEGF receptors (VEGFR1, VEGFR2 and VEGFR3) or one of two neuropilins (NP-1 and NP- 2). The VEGFRs are all part of the flt tyrosine kinase receptor family and each contain a conserved intracellular tyrosine kinase domain, transmembrane domain and seven extracellular immunoglobulins. The binding sites for each of these receptors exist separately on each end of a VEGF dimer interface, and stimulation by the ligand initiates either the homo or heterodimerization of the receptor.
The resulting signal transduction from the dimerization stimulates transphosphorylation of the intracellular tyrosine kinase domain and stimulation of associated downstream cascades including those of P13K, MAPK and PKC. Experiments that crosslinked VEGF to associated proteins lead to the discovery that VEGF also interacted with the neuronal receptors NP-1 and NP-2. These receptors in contrast to the VEGFRs recognize a domain that is specific to exon 7 and therefore have a much more limited interaction as this domain is only conserved in some splice variants of VEGF-A and VEGF-B. Many of the above receptors have accumulated various names over time and can bind different combinations of the VEGF ligands. Once ligand bound, VEGFR-2, the major VEGF receptor involved in VEGF-mediated cell growth and angiogenesis, activates downstream signaling pathways, including mitogen activated protein kinase (MAPK) also known as extracellular signal-regulated kinase 1/2 (ERK 1/2). Recent reports indicated that a number of cancers including breast, prostate, leukemia, pancreatic, and ovarian, express VEGF receptors, VEGFR-1, VEGFR-2 and neuropilin, that function in an autocrine loop to promote tumor cell growth, migration, and survival.
1. Leung D W, Cachianes G, Kuang W J, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen[J]. Science, 1989, 246(4935): 1306-1309.
2. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis[J]. Recent progress in hormone research, 1999, 55: 15-35; discussion 35-6.