VEGF-C

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VEGF-C

Existing structure data : PDB  2X1W , PDB  2X1X , PDB  4BSK

Properties of human protein
Mass / length primary structure 419 amino acids , 46,883 Da
Identifier
External IDs
Orthologue (human)
Entrez 7424
Ensemble ENSG00000150630
UniProt P49767
Refseq (mRNA) NM_005429.5
Refseq (protein) NP_005420.1
PubMed search 7424

3D-model of the VEGF-C protein based on the crystal structure 2X1W. The (crystallized) part of VEGF-C shown here exclusively comprises the VEGF homology domain .
Domain organization of the VEGF-C protein
Biosynthesis of the VEGF-C protein. A simplified scheme of the enzymatic cuts that lead to the activation of VEGF-C is shown. The numbers refer to the approximate molar mass of the different forms (in kDa). Glycosylation sites are shown in green and the central domain cysteines in yellow.

Vascular Endothelial Growth Factor C (VEGF-C) is a protein molecule that functions as a growth factor . It belongs to the group of the Platelet Derived Growth Factor / Vascular Endothelial Growth Factor (PDGF / VEGF) family.

Functions

The main function of VEGF-C is to stimulate the growth of lymphatic vessels ( lymphangiogenesis ). During embryonic development , VEGF-C is necessary for the development of the lymphatic system and in the adult organism for its maintenance and for lymphatic neoplasms, which are caused by e.g. B. in wound healing and in the menstrual cycle , but also take place in cancer . VEGF-C acts on the cells that form the inner wall layer (intima) of the lymphatic vessels, the so-called lymphatic endothelial cells (LECs).

The effect of VEGF-C is through the receptors Vascular Endothelial Growth Factor Receptor-3 (VEGF-Receptor-3, VEGFR-3 or FLT4) and Vascular Endothelial Growth Factor Receptor-2 (VEGF-Receptor-2, VEGFR-2 or KDR ), which are located on the cell surface of the endothelial cells and which can recognize VEGF-C molecules (according to the lock and key principle ). When VEGF-C is recognized by VEGFR-2 or VEGFR-3, the cells react with growth, cell division and targeted movement in the direction of the highest VEGF-C concentration ( chemotaxis , cell migration ). VEGF-C was discovered in 1996 in Kari Alitalo's laboratory as a ligand for VEGFR-3. Soon afterwards it could be shown experimentally that VEGF-C stimulates the growth of the lymph vessels. However, under certain circumstances VEGF-C can also regulate the growth of blood vessels and their permeability. The effect on blood vessels can be mediated by the primary receptor VEGFR-3 or by the secondary receptor VEGFR-2. In addition to the effects on lymph and blood vessels, VEGF-C is also involved in the development of the nervous system and the regulation of blood pressure.

biosynthesis

VEGF-C in humans by VEGF - gene encodes, located on the chromosome segment is 4q34. VEGF-C is a secreted protein and is released into the environment of the cell after it is generated. Various forms of VEGF-C are produced by enzymatic cleavage . After the formation of the VEGF-C during the translation of VEGF-C initially consists of three sections ( domains ): the central -VEGF homology domain (VHD), the N -terminal domain (also N -terminal propeptide called) and the C - terminal domain (also called C -terminal propeptide or silk homology domain). This form is called unprocessed VEGF-C and has a mass of about 58 kDa . The first enzymatic cleavage takes place within the cell between the VHD and the C-terminal domain and is carried out by proprotein convertases . Despite this cleavage, the two cleavage products remain connected to one another by disulfide bridges . This form is called the intermediate form or pro-VEGF-C . The two disulphide bonded split polypeptide chains have a mass of 29 and 31 kDa. Although this form can already bind the VEGFR-3 receptor , it cannot yet activate it. In order to obtain active VEGF-C, another cleavage must first take place between the N -terminal propeptide and the VHD. This cleavage can be done either by ADAMTS3 , plasmin , KLK3 / PSA or cathepsin D. With an increasing degree of processing, the affinity of VEGF-C for its receptors VEGFR-2 and VEGFR-3 increases. Only the fully processed, active VEGF-C has a high affinity for the VEGF receptor-2.

Relationship to VEGF-D

Structurally and functionally, VEGF-D (also known as c- fos- induced growth factor / FIGF) is most similar to VEGF-C. However, VEGF-C is absolutely necessary for the development of the lymphatic system , while the loss of VEGF-D does not seem to cause any problems at least in mice. It is doubtful whether this is also the case in humans because there are a number of important differences between human VEGF-D and VEGF-D from mice.

Disease relevance

In a minority of lymphedema patients, a mutated VEGFC gene is the cause of the disease, and VEGF-C is a potential drug for the treatment of lymphedema, although the underlying gene mutation is more often in the VEGF receptor -3 than in VEGF-C itself . Because only one of the two FLT4 alleles is mutated in hereditary lymphedema type 1 , not all VEGFR-3 molecules are inoperable . It is assumed that large amounts of VEGF-C can compensate for the consequences of the mutation through increased activation of the remaining functional receptors. For this reason, VEGF-C is being developed as a drug against lymphedema under the name Lymfactin . VEGF-C can also indirectly cause lymphedema: In the rare hereditary disease Hennekam syndrome , a mutated CCBE1 protein can no longer support the ADAMTS3 enzyme in activating VEGF-C. While a lack of active VEGF-C results in lymphedema, an excess of VEGF-C can also be problematic because it can promote tumor angiogenesis and metastasis . VEGF-C can have a direct angiogenic effect on blood vessels and, via increased lymphangiogenesis, it can promote the formation of metastases.

evolution

The PDGF family is so closely related to the VEGF family that the two are mostly grouped together as the PDGF / VEGF family. In invertebrates , the molecules of these two families cannot be easily distinguished from one another and they are therefore collectively referred to as PVFs (PDGF / VEGF-like growth factors). The comparison of human VEGFs with the PVFs allows conclusions to be drawn about the primeval precursor molecules, which seem to be more similar to today's lymphangiogenic VEGFs (VEGF-C and VEGF-D) than to the other members of the VEGF family. Despite the great evolutionary distance, the PVFs can still interact with human VEGF receptors today. The PVFs in Drosophila melanogaster have functions in the migration of hemocytes and the PVF in the jellyfish Podocoryne carnea has functions in the development of the tentacles and gastrovascular apparatus. Nothing is known about the function of PVF-1 in the roundworm Caenorhabditis elegans .

literature

  • Rauniyar K, Jha SK, Jeltsch M: Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels . In: Frontiers in Bioengineering and Biotechnology . tape 6 , no. 7 , 2018, doi : 10.3389 / fbioe.2018.00007 ( frontiersin.org ).
  • Krebs R, Jeltsch M: The lymphangiogenic growth factors VEGF-C and VEGF-D. Part 1. Basics and embryonic development. In: Lymphology in Research and Practice . tape 17 , no. 1 , 2013, p. 30–37 ( jeltsch.org [PDF]).
  • Krebs R, Jeltsch M: The lymphangiogenic growth factors VEGF-C and VEGF-D. Part 2. The role of VEGF-C and VEGF-D in diseases of the lymphatic system. In: Lymphology in Research and Practice . tape 17 , no. 2 , 2013, p. 96-104 ( jeltsch.org [PDF]).
  • Orpana A, Salven P: Angiogenic and lymphangiogenic molecules in hematological malignancies . In: Leukemia & Lymphoma . tape 43 , no. 2 , 2002, p. 219-24 , doi : 10.1080 / 10428190290005964 .
  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases . In: The EMBO Journal . tape 15 , no. 2 , 1996, p. 290-98 .
  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases . In: The EMBO Journal . tape 15 , no. 7 , 1996, pp. 1751 .
  • 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: Novel human vascular endothelial growth factor genes VEGF-B and VEGF -C localize to chromosomes 11q13 and 4q34, respectively . In: Circulation . tape 93 , no. 6 , 1996, pp. 1079-82 , doi : 10.1161 / 01.cir.93.6.1079 .
  • Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI: Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4 . In: Proceedings of the National Academy of Sciences . tape 93 , no. 5 , 1996, pp. 1988-92 , doi : 10.1073 / pnas.93.5.1988 .
  • Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K: Proteolytic processing regulates receptor specificity and activity of VEGF-C . In: The EMBO Journal . tape 16 , no. 13 , 1997, pp. 3898-911 , doi : 10.1093 / emboj / 16.13.3898 .
  • 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: Characterization of murine Flt4 ligand / VEGF-C . In: Oncogene . tape 15 , no. 5 , 1997, pp. 613-8 , doi : 10.1038 / sj.onc.1201191 .
  • Dunk C, Ahmed A: Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast . In: Histology and Histopathology . tape 16 , no. 2 , 2001, p. 359-75 .
  • Dias S, Choy M, Alitalo K, Rafii S: Vascular endothelial growth factor (VEGF) -C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy . In: Blood . tape 99 , no. 6 , 2002, pp. 2179-84 , doi : 10.1182 / blood.V99.6.2179 .
  • Ueda M, Terai Y, Yamashita Y, Kumagai K, Ueki K, Yamaguchi H, Akise D, Hung YC, Ueki M: Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas . In: International Journal of Cancer . tape 98 , no. 3 , 2002, p. 335-43 , doi : 10.1002 / ijc.10193 .
  • Witte D, Thomas A, Ali N, Carlson N, Younes M: Expression of the vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C in human colorectal adenocarcinoma . In: Anticancer Research . tape 22 , no. 3 , 2002, p. 1463-6 .
  • Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D: Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis . In: The American Journal of Pathology . tape 161 , no. 3 , 2002, p. 947-56 , doi : 10.1016 / S0002-9440 (10) 64255-1 .
  • Shin HY, Smith ML, Toy KJ, Williams PM, Bizios R, Gerritsen ME: VEGF-C mediates cyclic pressure-induced endothelial cell proliferation . In: Physiological Genomics . tape 11 , no. 3 , 2002, p. 245-51 , doi : 10.1152 / physiolgenomics.00068.2002 .
  • Yu DH, Wen YM, Sun JD, Wei SL, Xie HP, Pang FH: Relationship among the expression of vascular endothelial growth factor-C (VEGF-C), angiogenesis, lymphangiogenesis, and lymphatic metastasis in oral cancer] . In: Ai Zheng / Chinese Journal of Cancer . tape 21 , no. 3 , 2002, p. 319-22 .
  • Nakashima T, Kondoh S, Kitoh H, Ozawa H, Okita S, Harada T, Shiraishi K, Ryozawa S, Okita K: Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis . In: International Journal of Molecular Medicine . tape 11 , no. 1 , 2003, p. 33-9 , doi : 10.3892 / ijmm.11.1.33 .
  • Tsai PW, Shiah SG, Lin MT, Wu CW, Kuo ML: 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 . In: Journal of Biological Chemistry . tape 278 , no. 8 , 2003, p. 5750-9 , doi : 10.1074 / jbc.M204863200 .
  • Masood R, Kundra A, Zhu S, Xia G, Scalia P, Smith DL, Gill PS: Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops . In: International Journal of Cancer . tape 104 , no. 5 , 2003, p. 603-10 , doi : 10.1002 / ijc.10996 .
  • Ohno M, Nakamura T, Kunimoto Y, Nishimura K, Chung-Kang C, Kuroda Y: Lymphagenesis correlates with expression of vascular endothelial growth factor-C in colorectal cancer . In: Oncology Reports . tape 10 , no. 4 , 2004, p. 939-43 , doi : 10.3892 / or.10.4.939 .

Individual evidence

  1. ↑ Leppänen VM, Prota AE, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, Lankinen H, Goldman A, Ballmer-Hofer K, Alitalo K: Structural determinants of growth factor binding and specificity by VEGF receptor 2 . In: Proceedings of the National Academy of Sciences . tape 107 , no. 6 , 2010, p. 2425-2430 , doi : 10.1073 / pnas.0914318107 .
  2. ↑ Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases . In: The EMBO Journal . tape 15 , no. 2 , 1996, p. 290-298 .
  3. ↑ Oh SJ, Jeltsch MM, Birkenhäger R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J: VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane . In: Developmental Biology . tape 188 , no. 1 , 1997, p. 96-109 , doi : 10.1006 / dbio.1997.863 .
  4. ↑ Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K: Hyperplasia of lymphatic vessels in VEGF-C transgenic mice . In: Science . tape 276 , no. 5317 , 1997, pp. 1423-1425 , doi : 10.1126 / science.276.5317.1423 .
  5. ↑ a b c Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K: Proteolytic processing regulates receptor specificity and activity of VEGF-C . In: The EMBO Journal . tape 16 , no. 13 , 1997, pp. 3898-3911 , doi : 10.1093 / emboj / 16.13.3898 .
  6. ↑ a b 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: Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation . In: Nature . tape 454 , no. 7204 , 2008, p. 656–660 , doi : 10.1038 / nature07083 .
  7. ↑ 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: VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain . In: Nature Neuroscience . tape 9 , no. 3 , 2006, p. 340-348 , doi : 10.1038 / nn1646 .
  8. ↑ 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: Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism . In: Nature Medicine . tape 15 , no. 5 , 2009, p. 545-552 , doi : 10.1038 / nm . 1960 .
  9. ↑ 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: Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively . In: Circulation . tape 93 , no. 6 , 1996, pp. 1079-1082 , doi : 10.1161 / 01.CIR.93.6.1079 .
  10. ↑ Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, Seidah NG, Khatib AM: The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis . In: The Journal of Clinical Investigation . tape 111 , no. 11 , 2003, p. 1723-1732 , doi : 10.1172 / JCI17220 .
  11. ↑ a b c Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K: CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation . In: Circulation . tape 129 , no. 19 , 2014, pp. 1962–1971 , doi : 10.1161 / CIRCULATIONAHA.113.002779 .
  12. Jump up ↑ McColl BK, Baldwin ME, Roufail S, Freeman C, Moritz RL, Simpson RJ, Alitalo K, Stacker SA, Achen MG: Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D . In: The Journal of Experimental Medicine . tape 198 , no. 6 , 2003, p. 863–868 , doi : 10.1084 / jem.20030361 .
  13. ↑ Sawan Kumar Jha, Khushbu Rauniyar, Ewa Chronowska, Kenny Mattonet, Eunice Wairimu Maina, Hannu Koistinen, Ulf-Håkan Stenman, Kari Alitalo, Michael Jeltsch: KLK3 / PSA and cathepsin D activate VEGF-C and VEGF-D . In: eLife . 8, May 17, 2019, ISSN  2050-084X , pp. -44478. doi : 10.7554 / eLife.44478 . Retrieved May 18, 2019.
  14. ↑ Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA: Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) . In: Proceedings of the National Academy of Sciences . tape 95 , no. 2 , 1998, p. 548-553 .
  15. ↑ Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins . In: Nature Immunology . tape 5 , no. 1 , 2004, p. 74-80 , doi : 10.1038 / ni1013 .
  16. ↑ Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG: Vascular endothelial growth factor D is dispensable for development of the lymphatic system . In: Molecular and Cellular Biology . tape 25 , no. 6 , 2005, p. 2441-2449 , doi : 10.1128 / MCB.25.6.2441-2449.2005 .
  17. ↑ Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG: The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man . In: The Journal of Biological Chemistry . tape 276 , no. 22 , 2001, p. 19166-19171 , doi : 10.1074 / jbc.M100097200 .
  18. ↑ Balboa-Beltran E, Fernández-Seara MJ, Pérez-Muñuzuri A, Lago R, García-Magán C, Couce ML, Sobrino B, Amigo J, Carracedo A, Barros F: A novel stop mutation in the vascular endothelial growth factor C gene (VEGFC) results in Milroy-like disease . In: Journal of Medical Genetics . tape 51 , no. 7 , 2014, p. –2013–102020 , doi : 10.1136 / jmedgenet-2013-102020 .
  19. ↑ Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K: Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin . In: Circulation Research . tape 88 , no. 6 , 2001, p. 623-629 , doi : 10.1161 / 01.RES.88.6.623 .
  20. ↑ Honkonen KM, Visuri MT, Tervala TV, Halonen PJ, Koivisto M, Lähteenvuo MT, Alitalo KK, Ylä-Herttuala S, Saaristo AM: Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema . In: Annals of Surgery . tape 257 , no. 5 , 2013, p. 961-967 , doi : 10.1097 / SLA.0b013e31826ed043 .
  21. ↑ Brouillard P, Boon L, Vikkula M: Genetics of lymphatic anomalies . In: The Journal of Clinical Investigation . tape 124 , no. 3 , 2014, p. 898-904 , doi : 10.1172 / JCI71614 .
  22. ↑ Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K: A model for gene therapy of human hereditary lymphedema . In: Proceedings of the National Academy of Sciences . tape 98 , no. 22 , 2001, p. 12677-12682 , doi : 10.1073 / pnas.221449198 .
  23. ↑ Herantis Pharma: Lymfactin® for lymphedema . 2014 ( herantis.com ).
  24. ↑ Jha SK, Rauniyar K, Karpanen T, Leppänen VM, Brouillard P, Vikkula M, Alitalo K, Jeltsch M: Efficient Activation of the Lymphangiogenic Growth Factor VEGF-C Requires the C-Terminal Domain of VEGF-C and the N-Terminal Domain of CCBE1 . In: Scientific Reports . tape 7 , no. 1 , 2017, p. 4916 , doi : 10.1038 / s41598-017-04982-1 .
  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: Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization . In: Cancer Cell . tape 18 , no. 6 , 2010, p. 630-640 , doi : 10.1016 / j.ccr.2010.11.001 .
  26. ↑ 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: Vascular endothelial growth factor-C- mediated lymphangiogenesis promotes tumor metastasis . In: The EMBO Journal . tape 20 , no. 4 , 2001, p. 672-682 , doi : 10.1093 / emboj / 20.4.672 .
  27. ↑ a b 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 . In: FASEB Journal . tape 20 , no. 2 , 2006, p. 227-233 , doi : 10.1096 / fj.05-4147com .
  28. ↑ Heino TI, Kärpänen T, Wahlström G, Pulkkinen M, Eriksson U, Alitalo K, Roos C: The Drosophila VEGF receptor homolog is expressed in hemocytes . In: Mechanisms of Development . tape 109 , no. 1 , 2001, p. 69-77 , doi : 10.1016 / S0925-4773 (01) 00510-X .
  29. ↑ 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 . In: Developmental Dynamics . tape 231 , no. 2 , 2004, p. 303-312 , doi : 10.1002 / dvdy.20139 .