Vascular endothelial growth factor C

Vascular endothelial growth factor C (VEGF-C) is a is_associated_with::protein that is a member of the is_associated_with::platelet-derived growth factor / is_associated_with::vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC is_associated_with::gene, which is located on chromosome 4q34.

Functions
It's main function is in is_associated_with::lymphangiogenesis, where it acts on is_associated_with::lymphatic is_associated_with::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. The effect on blood vessels can be mediated via its primary receptor VEGFR-3 or its secondary receptor VEGFR-2. Apart from vascular targets, VEGF-C is also important for neural development and blood pressure regulation.

Biosynthesis
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. The first cleavage (which happens already before secretion) occurs between the VHD and the C-terminal domain and is mediated by is_associated_with::proprotein convertases. However, the resulting protein is still held together by is_associated_with::disulfide bonds and remains inactive (although it can bind already VEGFR-3). This form is referred to as "intermediate form" or pro-VEGF-C and it consists of two polypeptide chains of 29 and 31 kDa. In order to activate VEGF-C, a second cleavage has to occur between the N-terminal propeptide and the VHD. This cleavage can be performed either by is_associated_with::ADAMTS3 or is_associated_with::plasmin. With progressing maturation, the affinity of VEGF-C for both VEGFR-2 and VEGFR-3 increases and only the fully processed, mature forms of VEGF-C have a significant affinity for VEGFR-2.

Relationship to VEGF-D
The closest structural and functional relative of VEGF-C is is_associated_with::VEGF-D. However, at least in mice, VEGF-C is absolutely essential for the development of the is_associated_with::lymphatic system, whereas VEGF-D appears to be not necessary at all. Whether this holds true for humans is unknown, because there are major differences between human and mouse VEGF-D.

Disease relevance
In a minority of lymphedema patients, the condition is caused by mutations in the VEGFC gene and VEGF-C is a potential treatment for is_associated_with::lymphedema, even though the underlying molecular cause appears more often in the VEGF-Receptor-3 instead of VEGF-C itself. Because in is_associated_with::Milroy's disease (Hereditary lymphedema type I), only one allele is mutated, not all VEGFR-3 molecules are non-functional and it is thought, that high amounts of VEGF-C can compensate for the mutated, nonfunctional receptors by increasing the signaling levels of the remaining functional receptors. Therefore 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 is_associated_with::Hennekam syndrome can result from the inability of the mutated is_associated_with::CCBE1 to assist the is_associated_with::ADAMTS3 protease in activating VEGF-C. While a lack of VEGF-C results in lymphedema, too much VEGF-C is implicated in tumor is_associated_with::angiogenesis and is_associated_with::metastasis. VEGF-C can act directly on blood vessels to promote tumor angiogenesis and it can promote is_associated_with::lymphangiogenesis, which might result in increased metastasis.

Evolution
The PDGF family is so closely related to the VEGF family that the two are sometimes grouped together as the PDGF/VEGF family. In invertebrates, molecules from this families are not easily distinguished from each other and are collectively referred to as PVFs (PDGF/VEGF-like growth factors. The comparison of human VEGFs with these PVFs allows conclusions on the structure of the ancestral molecules, which appear more closely related to today's lymphangiogenic VEGF-C than to the other members of the VEGF family and despite their large evolutionary distance are still able to interact with human VEGF receptors. The PVFs in is_associated_with::Drosophila melanogaster have functions for the migration of is_associated_with::hemocytes and the PVFs in the jellyfish is_associated_with::Podocoryne carnea for the development of the tentacles and the gastrovascular apparatus. However, the function of the PVF-1 of the nematode is_associated_with::Caenorhabditis elegans is unknown