Vascular Endothelial Growth Factors (VEGF)

Jennifer Fries

BioFiles 2009, 4.5, 26

Vascular endothelial growth factor (VEGF) is a family of closely related growth factors having a conserved pattern of eight cysteine residues and sharing common VEGF receptors. Originally known simply as VEGF, vasculotropin (VAS) or vascular permeability factor (VPF), this factor is now sometimes called VEGF-A. Four additional family members (placental growth factor, PlGF; VEGF-B; VEGF-C; and VEGF-D) have been identified to date.

VEGF-A (VEGF) is a potent growth factor for blood vessel endothelial cells, showing pleiotropic responses that facilitate cell migration, proliferation, tube formation, and survival. It is also one of the most potent permeability factors, so that VEGF-A is a common link of inflammation, permeability and angiogenesis. VEGF-A mRNA expression patterns are closely related to proliferation of blood vessels during the developing embryo and wound healing or in the ovary. Local hypoxia is a potent inducer of VEGF-A expression from adjacent cells but it is not synthesized in endothelial cells, indicating a paracrine regulation of vessel formation. In the developing embryo VEGF-A mRNA is expressed by cells within tissues undergoing capillarization. In most adult tissues the level of VEGF-A expression is low except in the kidney (Bowman’s capsule podocytes). Expression of VEGF-A can be induced in macrophages, T cells, astrocytes, osteoblasts, smooth muscle cells, fibroblasts, endothelial cells, cardiomyocytes, skeletal muscle cells and keratinocytes. It is also expressed in a variety of human tumors. Due to alternative splicing of a single gene, VEGF-A may exist in four isoforms, designated by their expected final amino acid length (VEGF121, VEGF165, VEGF189 and VEGF206). These isoforms show similar biological activities but bind with different affinities to the heparin and result in different secretion patterns. The smallest isoform (VEGF121) is secreted and completely diffusible, the largest (VEGF206) is almost completely attached to the extracellular matrix, and the other two show intermediate heparin binding affinities. VEGF-A exerts its actions through two receptors (VEGFR-1 and VEGFR-2).

PlGF is expressed in the placenta and somewhat less in the heart, lung and thyroid gland. Placentally expressed PlGF may act as an autocrine on trophoblasts, which express both PlGF and its receptor (VEGFR-1). Since these cells also make VEGF-A, natural heterodimers (PlGF/VEGF-A) have also been detected. Two alternatively spliced isoforms of PlGF have been identified. Hypoxia does not induce PlGF synthesis, but the formation of heterodimers would be affected due to hypoxic control over VEGF-A expression. VEGF-B is largely cellassociated and expressed mostly in the heart, skeletal muscle, brain and kidney. It is often co-expressed with VEGF-A and heterodimers of A/B have been detected. VEGF-B expression is not regulated by hypoxia. The long half-life of its mRNA (>8 hours) suggests a chronic rather than acute regulation. VEGF-B exerts its actions through one receptor (VEGFR-1).VEGF-C, also called VEGF-related factor (VRP) or VEGF-2, in the adult is expressed primarily in the heart, placenta, lung, kidney, muscle, ovary and small intestine. During embryo development it is expressed in the cephalic mesenchyme, tail region and allantois and along the somites. VEGF-C may play roles in the development of the veinous and lymphatic vasculature systems. VEGF-C exerts its actions through two receptors (VEGFR-2 and VEGFR-3). VEGF-D, also called c-fos induced growth factor (FIGF), is a VEGF homologue induced by c-fos. It is expressed in adult lung, heart and small intestine and in fetal lung. It is reported mildly mitogenic for endothelial cells. VEGF-D and VEGF-C share 23% amino acid sequence homology. VEGF-D exerts its actions through two receptors (VEGFR-2 and VEGFR-3).

References

1. Ferrara N, Park J, Nicola N. 1994. Vascular endothelial growth factor (VEGF), in Guidebook to Cytokines and Their Receptors. New York: Oxford Press.

2. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. 1998. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proceedings of the National Academy of Sciences. 95(2):548-553. https://doi.org/10.1073/pnas.95.2.548

3. Carmeliet P, Collen D. 1999. Role of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptors in Vascular Development.133-158. https://doi.org/10.1007/978-3-642-59953-8_7

4. NEUFELD G, COHEN T, GENGRINOVITCH S, POLTORAK Z. 1999. Vascular endothelial growth factor (VEGF) and its receptors. FASEB j.. 13(1):9-22. https://doi.org/10.1096/fasebj.13.1.9