The main function of VEGF-C is in lymphangiogenesis, where it acts on lymphaticendothelial 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. It has been suggested that VEGFC is a morphogen but not a chemotactic factor for lymphatic endothelial cell precursors.
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 proprotein convertases. However, the resulting protein is still held together by 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 ADAMTS3, plasmin, KLK3/PSA or cathepsin D. 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 VEGF-D. However, at least in mice, VEGF-C is absolutely essential for the development of the lymphatic system, whereas VEGF-D appears to be unnecessary. Whether this holds true for humans is unknown, because there are major differences between human and mouse VEGF-D.
In a minority of lymphedema patients, the condition is caused by mutations in the VEGFC gene and 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. Because in 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 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.
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 Drosophila melanogaster have functions for the migration of hemocytes and the PVFs in the jellyfish Podocoryne carnea for the development of the tentacles and the gastrovascular apparatus. However, the function of the PVF-1 of the nematode Caenorhabditis elegans is unknown
^Oh SJ, Jeltsch MM, Birkenhäger R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (Aug 1997). "VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane". Developmental Biology. 188 (1): 96–109. doi:10.1006/dbio.1997.8639. PMID9245515.
^Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (May 1997). "Hyperplasia of lymphatic vessels in VEGF-C transgenic mice". Science. 276 (5317): 1423–1425. doi:10.1126/science.276.5317.1423. PMID9162011.
^ abTammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (Jul 2008). "Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation". Nature. 454 (7204): 656–660. doi:10.1038/nature07083. PMID18594512.
^Le Bras B, Barallobre MJ, Homman-Ludiye J, Ny A, Wyns S, Tammela T, Haiko P, Karkkainen MJ, Yuan L, Muriel MP, Chatzopoulou E, Bréant C, Zalc B, Carmeliet P, Alitalo K, Eichmann A, Thomas JL (Mar 2006). "VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain". Nature Neuroscience. 9 (3): 340–348. doi:10.1038/nn1646. PMID16462734.
^Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J (May 2009). "Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism". Nature Medicine. 15 (5): 545–552. doi:10.1038/nm.1960. PMID19412173.
^Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (Jan 2004). "Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins". Nature Immunology. 5 (1): 74–80. doi:10.1038/ni1013. PMID14634646.
^Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG (Jun 2001). "The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man". The Journal of Biological Chemistry. 276 (22): 19166–19171. doi:10.1074/jbc.M100097200. PMID11279005.
^Balboa-Beltran E, Fernández-Seara MJ, Pérez-Muñuzuri A, Lago R, García-Magán C, Couce ML, Sobrino B, Amigo J, Carracedo A, Barros F (Jul 2014). "A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease". Journal of Medical Genetics. 51 (7): 475–8. doi:10.1136/jmedgenet-2013-102020. PMID24744435.
^Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K (Mar 2001). "Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin". Circulation Research. 88 (6): 623–629. doi:10.1161/01.RES.88.6.623. PMID11282897.
^Honkonen KM, Visuri MT, Tervala TV, Halonen PJ, Koivisto M, Lähteenvuo MT, Alitalo KK, Ylä-Herttuala S, Saaristo AM (May 2013). "Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema". Annals of Surgery. 257 (5): 961–967. doi:10.1097/SLA.0b013e31826ed043. PMID23013803.
^ abTarsitano M, De Falco S, Colonna V, McGhee JD, Persico MG (Feb 2006). "The C. elegans pvf-1 gene encodes a PDGF/VEGF-like factor able to bind mammalian VEGF receptors and to induce angiogenesis". FASEB Journal. 20 (2): 227–233. doi:10.1096/fj.05-4147com. PMID16449794.
^Heino TI, Kärpänen T, Wahlström G, Pulkkinen M, Eriksson U, Alitalo K, Roos C (Nov 2001). "The Drosophila VEGF receptor homolog is expressed in hemocytes". Mechanisms of Development. 109 (1): 69–77. doi:10.1016/S0925-4773(01)00510-X. PMID11677054.
^Seipel K, Eberhardt M, Müller P, Pescia E, Yanze N, Schmid V (Oct 2004). "Homologs of vascular endothelial growth factor and receptor, VEGF and VEGFR, in the jellyfish Podocoryne carnea". Developmental Dynamics. 231 (2): 303–312. doi:10.1002/dvdy.20139. PMID15366007.
Fitz LJ, Morris JC, Towler P, Long A, Burgess P, Greco R, Wang J, Gassaway R, Nickbarg E, Kovacic S, Ciarletta A, Giannotti J, Finnerty H, Zollner R, Beier DR, Leak LV, Turner KJ, Wood CR (Jul 1997). "Characterization of murine Flt4 ligand/VEGF-C". Oncogene. 15 (5): 613–8. doi:10.1038/sj.onc.1201191. PMID9247316.
Dunk C, Ahmed A (Apr 2001). "Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast". Histology and Histopathology. 16 (2): 359–75. PMID11332691.
Dias S, Choy M, Alitalo K, Rafii S (Mar 2002). "Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy". Blood. 99 (6): 2179–84. doi:10.1182/blood.V99.6.2179. PMID11877295.
Ueda M, Terai Y, Yamashita Y, Kumagai K, Ueki K, Yamaguchi H, Akise D, Hung YC, Ueki M (Mar 2002). "Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas". International Journal of Cancer. 98 (3): 335–43. doi:10.1002/ijc.10193. PMID11920583.
Witte D, Thomas A, Ali N, Carlson N, Younes M (2002). "Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma". Anticancer Research. 22 (3): 1463–6. PMID12168824.
Yu DH, Wen YM, Sun JD, Wei SL, Xie HP, Pang FH (Mar 2002). "[Relationship among expression of vascular endothelial growth factor-C(VEGF-C), angiogenesis, lymphangiogenesis, and lymphatic metastasis in oral cancer]". AI Zheng = Aizheng = Chinese Journal of Cancer. 21 (3): 319–22. PMID12452004.
Nakashima T, Kondoh S, Kitoh H, Ozawa H, Okita S, Harada T, Shiraishi K, Ryozawa S, Okita K (Jan 2003). "Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis". International Journal of Molecular Medicine. 11 (1): 33–9. doi:10.3892/ijmm.11.1.33. PMID12469214.
Tsai PW, Shiah SG, Lin MT, Wu CW, Kuo ML (Feb 2003). "Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway". The Journal of Biological Chemistry. 278 (8): 5750–9. doi:10.1074/jbc.M204863200. PMID12471041.
Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, Gill PS (May 2003). "Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops". International Journal of Cancer. 104 (5): 603–10. doi:10.1002/ijc.10996. PMID12594815.
Ohno M, Nakamura T, Kunimoto Y, Nishimura K, Chung-Kang C, Kuroda Y (2004). "Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer". Oncology Reports. 10 (4): 939–43. doi:10.3892/or.10.4.939. PMID12792749.