Vascular endothelial growth factor C explained

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.[1]

Functions

The main function of VEGF-C is to promote the growth of lymphatic vessels (lymphangiogenesis). 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.[2] Soon thereafter, it was shown to be a specific growth factor for lymphatic vessels in a variety of models.[3] [4] 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[5] or its secondary receptor VEGFR-2. Apart from vascular targets, VEGF-C is also important for neural development[6] and blood pressure regulation.[7]

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).[8] 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.[9] However, the resulting protein is still held together by disulfide bonds and remains inactive (although it can bind already VEGFR-3).[10] 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,[10] plasmin,[11] KLK3/PSA or cathepsin D.[12] 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.[8]

Relationship to VEGF-D

The closest structural and functional relative of VEGF-C is VEGF-D.[13] However, at least in mice, VEGF-C is absolutely essential for the development of the lymphatic system,[14] whereas VEGF-D appears to be unnecessary.[15] Whether this holds true for humans is unknown, because there are major differences between human and mouse VEGF-D.[16]

Disease relevance

In a minority of lymphedema patients, the condition is caused by mutations in the VEGFC gene[17] and VEGF-C is a potential treatment for lymphedema,[18] [19] even though the underlying molecular cause appears more often in the VEGF-Receptor-3 instead of VEGF-C itself.[20] 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.[21] Therefore, VEGF-C is developed as a lymphedema drug under the name of Lymfactin.[22] 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.[10] While lack of VEGF-C results in lymphedema, VEGF-C production is implicated in tumor lymphangiogenesis and metastasis. Expression of VEGF-C by tumors induces peri-tumoral and intratumoral lymphangiogenesis what potently promotes metastatic dissemination of tumor cells.[23] [24] VEGF-C primarily stimulates lymphangiogenesis by activating VEGFR-3, yet under certain conditions it can also act directly on blood vessels to promote tumor angiogenesis.[5] [25]

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.[26] 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[27] and the PVFs in the jellyfish Podocoryne carnea for the development of the tentacles and the gastrovascular apparatus.[28] However, the function of the PVF-1 of the nematode Caenorhabditis elegans is unknown[26]

Further reading

Notes and References

  1. Paavonen K, Horelli-Kuitunen N, Chilov D, Kukk E, Pennanen S, Kallioniemi OP, Pajusola K, Olofsson B, Eriksson U, Joukov V, Palotie A, Alitalo K . 6 . Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively . Circulation . 93 . 6 . 1079–1082 . March 1996 . 8653826 . 10.1161/01.CIR.93.6.1079 .
  2. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K . 6 . A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases . The EMBO Journal . 15 . 2 . 290–298 . January 1996 . 8617204 . 449944 . 10.1002/j.1460-2075.1996.tb00359.x .
  3. Oh SJ, Jeltsch MM, Birkenhäger R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J . 6 . VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane . Developmental Biology . 188 . 1 . 96–109 . August 1997 . 9245515 . 10.1006/dbio.1997.8639 . free .
  4. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K . 6 . Hyperplasia of lymphatic vessels in VEGF-C transgenic mice . Science . 276 . 5317 . 1423–1425 . May 1997 . 9162011 . 10.1126/science.276.5317.1423 . 21835142 .
  5. Tammela 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 . 6 . Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation . Nature . 454 . 7204 . 656–660 . July 2008 . 18594512 . 10.1038/nature07083 . 2008Natur.454..656T . 2251527 .
  6. 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 . 6 . VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain . Nature Neuroscience . 9 . 3 . 340–348 . March 2006 . 16462734 . 10.1038/nn1646 . 24197350 .
  7. 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 . 6 . Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism . Nature Medicine . 15 . 5 . 545–552 . May 2009 . 19412173 . 10.1038/nm.1960 . 10526891 .
  8. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K . 6 . Proteolytic processing regulates receptor specificity and activity of VEGF-C . The EMBO Journal . 16 . 13 . 3898–3911 . July 1997 . 9233800 . 1170014 . 10.1093/emboj/16.13.3898 .
  9. Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, Seidah NG, Khatib AM . 6 . The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis . The Journal of Clinical Investigation . 111 . 11 . 1723–1732 . June 2003 . 12782675 . 156106 . 10.1172/JCI17220 .
  10. Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K . 6 . CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation . Circulation . 129 . 19 . 1962–1971 . May 2014 . 24552833 . 10.1161/CIRCULATIONAHA.113.002779 . free .
  11. McColl BK, Baldwin ME, Roufail S, Freeman C, Moritz RL, Simpson RJ, Alitalo K, Stacker SA, Achen MG . 6 . Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D . The Journal of Experimental Medicine . 198 . 6 . 863–868 . September 2003 . 12963694 . 2194198 . 10.1084/jem.20030361 .
  12. Jha SK, Rauniyar K, Chronowska E, Mattonet K, Maina EW, Koistinen H, Stenman UH, Alitalo K, Jeltsch M . 6 . KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D . eLife . 8 . 44478 . May 2019 . 31099754 . 6588350 . 10.7554/eLife.44478 . free .
  13. Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA . 6 . 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 of the United States of America . 95 . 2 . 548–553 . January 1998 . 9435229 . 18457 . 10.1073/pnas.95.2.548 . 1998PNAS...95..548A . free .
  14. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K . 6 . Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins . Nature Immunology . 5 . 1 . 74–80 . January 2004 . 14634646 . 10.1038/ni1013 . 22078757 .
  15. Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG . 6 . Vascular endothelial growth factor D is dispensable for development of the lymphatic system . Molecular and Cellular Biology . 25 . 6 . 2441–2449 . March 2005 . 15743836 . 1061605 . 10.1128/MCB.25.6.2441-2449.2005 .
  16. Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG . 6 . 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 . June 2001 . 11279005 . 10.1074/jbc.M100097200 . 41677159 . free .
  17. Balboa-Beltran E, Fernández-Seara MJ, Pérez-Muñuzuri A, Lago R, García-Magán C, Couce ML, Sobrino B, Amigo J, Carracedo A, Barros F . 6 . A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease . Journal of Medical Genetics . 51 . 7 . 475–478 . July 2014 . 24744435 . 10.1136/jmedgenet-2013-102020 . 6613861 .
  18. Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K . 6 . Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin . Circulation Research . 88 . 6 . 623–629 . March 2001 . 11282897 . 10.1161/01.RES.88.6.623 . 28806663 . free .
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  22. Web site: Herantis Pharma. Lymfactin® for lymphedema. 2014-07-21.
  23. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M . 6 . Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis . Nature Medicine . 7 . 2 . 192–198 . February 2001 . 11175850 . 10.1038/84643 . 26090359 .
  24. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS . 6 . Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis . The EMBO Journal . 20 . 4 . 672–682 . February 2001 . 11179212 . 145430 . 10.1093/emboj/20.4.672 .
  25. Tvorogov D, Anisimov A, Zheng W, Leppänen VM, Tammela T, Laurinavicius S, Holnthoner W, Heloterä H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala PM, Alitalo K . 6 . Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization . Cancer Cell . 18 . 6 . 630–640 . December 2010 . 21130043 . 10.1016/j.ccr.2010.11.001 . free .
  26. Tarsitano M, De Falco S, Colonna V, McGhee JD, Persico MG . 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 . February 2006 . 16449794 . 10.1096/fj.05-4147com . free . 31963203 .
  27. Heino TI, Kärpänen T, Wahlström G, Pulkkinen M, Eriksson U, Alitalo K, Roos C . The Drosophila VEGF receptor homolog is expressed in hemocytes . Mechanisms of Development . 109 . 1 . 69–77 . November 2001 . 11677054 . 10.1016/S0925-4773(01)00510-X . 14074572 .
  28. Seipel K, Eberhardt M, Müller P, Pescia E, Yanze N, Schmid V . Homologs of vascular endothelial growth factor and receptor, VEGF and VEGFR, in the jellyfish Podocoryne carnea . Developmental Dynamics . 231 . 2 . 303–312 . October 2004 . 15366007 . 10.1002/dvdy.20139 . 42930371 . free .

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