Research Area

VEGF Family


Overview

Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by cells that stimulate the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).

When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the retina of the eye and other parts of the body. Drugs such as aflibercept, bevacizumab, ranibizumab and pegaptanib sodium (macugen) can inhibit VEGF and control or slow those diseases.

Members of VEGF Family

The VEGF family comprises in mammals five members: VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C and VEGF-D. The latter ones were discovered later than VEGF-A, and, before their discovery, VEGF-A was called just VEGF. A number of VEGF-related proteins encoded by viruses (VEGF-E) and in the venom of some snakes (VEGF-F) have also been discovered.

Table 1. VEGF family related products

VEGF Family Ligands FIGF / VEGFD PGF VEGF
VEGFA VEGFB VEGFC
VEGF Family Receptors VEGFR1 / FLT1 VEGFR2 / KDR VEGFR3 / FLT4

  • VEGF-A

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene. This gene is a member of the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family and encodes a protein that is often found as a disulfide linked homodimer. VEGF-A shows prominent activity with vascular endothelial cells, primarily through its interactions with the VEGFR1 and -R2 receptors found in prominently on the endothelial cell membrane. Although, it does have effects on a number of other cell types (e.g., stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells). In vitro, VEGF-A has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.

VEGF Family

Figure 1. VEGF-A protein

  • VEGF-B

Vascular endothelial growth factor B also known as VEGF-B is a protein that, in humans, is encoded by the VEGF-B gene. VEGF-B is a growth factor that belongs to the vascular endothelial growth factor family. In contrast to VEGF-A, VEGF-B plays a less pronounced role in the vascular system: Whereas VEGF-A is important for the formation of blood vessels, such as during development or in pathological conditions; VEGF-B seems to play a role only in the maintenance of newly formed blood vessels during pathological conditions.

  • VEGF-C

Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34. VEGF-C is a dimeric, secreted protein, which undergoes a complex proteolytic maturation resulting in multiple processed forms. After translation, VEGF-C consists of three domains: the central VEGF homology domain (VHD), the N-terminal domain (propeptide) and a C-terminal domain (propeptide). It is referred to as "uncleaved VEGF-C" and has a size of approximately 58 kDa.

VEGF Family

Figure 2. VEGF-C protein

  • FIGF

C-fos-induced growth factor (FIGF) (or vascular endothelial growth factor D, VEGF-D) is a vascular endothelial growth factor that in humans is encoded by the FIGF gene. The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family and is active in angiogenesis, lymphangiogenesis, and endothelial cell growth. This secreted protein undergoes a complex proteolytic maturation, generating multiple processed forms that bind and activate VEGFR-2 and VEGFR-3 receptors. The structure and function of this protein is similar to those of vascular endothelial growth factor C.

  • PGF

Placental growth factor is a protein that in humans is encoded by the PGF gene. PGF is a member of the VEGF (vascular endothelial growth factor) sub-family - a key molecule in angiogenesis and vasculogenesis, in particular during embryogenesis. The main source of PGF during pregnancy is the placental trophoblast. PGF is also expressed in many other tissues, including the villous trophoblast.

VEGF Family

Figure 3. PGF protein

Cellular functions

VEGF-A is a glycosylated mitogen that specifically acts on endothelial cells and has various effects, including mediating increased vascular permeability, inducing angiogenesis, vasculogenesis and endothelial cell growth, promoting cell migration, and inhibiting apoptosis. Alternatively spliced transcript variants, encoding either freely secreted or cell-associated isoforms, have been characterized. VEGF-A mediates the growth of new blood vessels from pre-existing vessels (angiogenesis) by binding to the cell surface receptors VEGFr1 and VEGFr2, two tyrosine kinases located in endothelial cells of the cardiovascular system. These two receptors act through different pathways to contribute to endothelial cell proliferation and migration, and formation of tubular structures.

VEGF-B also plays an important role on several types of neurons. It is important for the protection of neurons in the retina and the cerebral cortex during stroke and of motoneurons during motor neuron diseases such as amyotrophic lateral sclerosis. VEGF-B exerts its effects via the FLT1 receptor. It has also been found to control endothelial uptake and transport of fatty acids in heart and skeletal muscle.

The main function of VEGF-C is in lymphangiogenesis, where it acts on lymphatic endothelial cells (LECs) primarily via its receptor VEGFR-3 promoting survival, growth and migration. It was discovered in 1996 as a ligand for the orphan receptor VEGFR-3. Soon thereafter, it was shown to be a specific growth factor for lymphatic vessels in a variety of models. However, in addition to its effect on lymphatic vessels, it can also promote the growth of blood vessels and regulate their permeability.

VEGF-D’s interactions with VEGFR-3 predominantly expressed in lymphatic vessels play a key role in restructuring lymphatic channel and hence, altering its functions related to fluid and cell transport along the conduits. VEGF-D has been established to be over-expressed in both tumor tissues and patients’ serum samples in several types of human cancer.

PGF plays a role in trophoblast growth and differentiation. Trophoblast cells, specifically extravillous trophoblast cells, are responsible for invading maternal arteries. Proper development of blood vessels in the placenta is crucial for proper embryonic development. Under normal physiologic conditions, PGF is also expressed at a low level in other organs including the heart, lung, thyroid, and skeletal muscle.

Role in disease

VEGFA is essential for adults during organ remodeling and diseases that involve blood vessels, for example, in wound healing, tumor angiogenesis, diabetic retinopathy, and age-related macular degeneration. Normally, if blood flow to the heart is compromised, over time, new blood vessels will develop, providing alternative circulation to the affected cells. The viability of the heart following severely restricted blood flow is dependent on the ability of the heart to provide this collateral circulation. Expression of VEGF-A has been found to be induced by myocardial ischemia and a higher level of expression of VEGF-A has been associated with better collateral circulation development during ischemia.

VEGF-C is a potential treatment for lymphedema, even though the underlying molecular cause appears more often in the VEGF-Receptor-3 instead of VEGF-C itself. VEGF-C is developed as a lymphedema drug under the name of lymfactin. Also indirectly VEGF-C can be responsible for hereditary lymphedema: The rare Hennekam syndrome can result from the inability of the mutated CCBE1 to assist the ADAMTS3 protease in activating VEGF-C. While a lack of VEGF-C results in lymphedema, too much VEGF-C is implicated in tumor angiogenesis and metastasis. VEGF-C can act directly on blood vessels to promote tumor angiogenesis and it can promote lymphangiogenesis, which might result in increased metastasis.

VEGF-D expression has been implicated with increased incidence of regional lymph node metastasis. In experimental mice study, genetically modified tumor cell that was forced to produce VEGF-D protein has been established to boost up regional lymph nodes metastases.

Placental growth factor-expression within human atherosclerotic lesions is associated with plaque inflammation and neovascular growth. Serum levels of PGF and sFlt-1 (soluble fms-like tyrosine kinase-1, also known as soluble VEGF receptor-1) are altered in women with preeclampsia. Studies show that in both early and late onset preeclampsia, maternal serum levels of sFlt-1 are higher and PGF lower in women presenting with preeclampsia. PGF is a potential biomarker for preeclampsia, a condition in which blood vessels in the placenta are too narrow, resulting in high blood pressure. As mentioned before, extravillous trophoblast cells invade maternal arteries. Improper differentiation may result in hypo-invasion of these arteries and thus failure to widen enough. Studies have found low levels of PGF in women who were diagnosed with preeclampsia later in their pregnancy.

References:

1. Palmer, Biff F.; Clegg, Deborah J. (2014). "Oxygen sensing and metabolic homeostasis". Molecular and Cellular Endocrinology. 397: 51–57. doi:10.1016/j.mce.2014.08.001
2. Tischer, E; Mitchell, R; Hartman, T. "The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing". The Journal of Biological Chemistry. 266 (18): 11947–54.
3. Dougher-Vermazen M, Hulmes JD, Böhlen P. "Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor". Biochem. Biophys. Res. Commun. 205 (1): 728–38.
4. Sun Y, Jin K, Childs JT, Xie L. "Increased severity of cerebral ischemic injury in vascular endothelial growth factor-B-deficient mice". J. Cereb. Blood Flow Metab. 24 (10): 1146–52.
5. Jeltsch M, Kaipainen A, Joukov V. "Hyperplasia of lymphatic vessels in VEGF-C transgenic mice". Science. 276 (5317): 1423–1425.

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