The role of VEGF165b in pathophysiology

Cell Adhesion and Migration

Volumn 6, Issue 6, 2012, Pages 561-568

  Peiris Pages̀, Maria ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

Age related macular degeneration; Alternative splicing; Angiogenesis; Cancer; Denys Drash syndrome; Diabetic retinopathy; Pre eclampsia; Systemic sclerosis

Indexed keywords

BEVACIZUMAB; MEMBRANE PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; PROTEIN KINASE C; SRSF1 PROTEIN; SRSF2 PROTEIN; SRSF6 PROTEIN; TRANSCRIPTION FACTOR E2F1; UNCLASSIFIED DRUG; VASCULOTROPIN 165; VASCULOTROPIN 165B; VASCULOTROPIN A; ISOPROTEIN; NUCLEAR PROTEIN; RNA BINDING PROTEIN; SERINE ARGININE RICH SPLICING PROTEINS; SERINE-ARGININE-RICH SPLICING PROTEINS; VASCULOTROPIN RECEPTOR 2; VEGFA PROTEIN, HUMAN;

AUTOPHOSPHORYLATION; BINDING AFFINITY; CARCINOGENESIS; CELL PROLIFERATION; COLORECTAL CANCER; CORRELATION ANALYSIS; DENYS DRASH SYNDROME; DIABETIC RETINOPATHY; DISEASE ASSOCIATION; DOWN REGULATION; ENZYME LINKED IMMUNOSORBENT ASSAY; EWING SARCOMA; EXON; GONAD DEVELOPMENT; HUMAN; IN VIVO STUDY; INHIBITION KINETICS; KIDNEY CARCINOMA; KIDNEY CORTEX; MELANOMA; NEOVASCULARIZATION (PATHOLOGY); NONHUMAN; PATHOPHYSIOLOGY; PODOCYTE; PREECLAMPSIA; PROSTATE CANCER; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REGULATORY MECHANISM; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; SYSTEMIC SCLEROSIS; TRANSCRIPTION INITIATION SITE; UPREGULATION; VITREOUS BODY; ALTERNATIVE RNA SPLICING; ANIMAL; CAPILLARY PERMEABILITY; GENETICS; GLOMERULONEPHRITIS; METABOLISM; NEOPLASM; PHOSPHORYLATION;

ALTERNATIVE SPLICING; ANIMALS; CAPILLARY PERMEABILITY; DENYS-DRASH SYNDROME; DIABETIC RETINOPATHY; GLOMERULONEPHRITIS; HUMANS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; NUCLEAR PROTEINS; PHOSPHORYLATION; PROTEIN ISOFORMS; RNA-BINDING PROTEINS; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

MLCS; MLOWN;

EID: 84872091893     PISSN: 19336918     EISSN: 19336926     Source Type: Journal    
DOI: 10.4161/cam.22439     Document Type: Review

References (58)

1. Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9:653-60; PMID:12778163; http://dx.doi.org/10.1038/nm0603-653
2. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9:669-76; PMID:12778165; http://dx.doi.org/10.1038/nm0603-669
3. Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 2002; 62:4123-31; PMID:12124351
4. Cébe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A, et al. A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci 2006; 63:2067-77; PMID:16909199; http://dx.doi.org/10.1007/s00018-006-6254-9
5. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13:9-22; PMID:9872925
6. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114:853-65; PMID:11181169
7. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991; 266:11947-54; PMID:1711045
8. Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 2004; 64:7822-35; PMID:15520188; http://dx.doi.org/10. 1158/0008-5472.CAN-04-0934
9. Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ. Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia 2005; 48:2422-7; PMID:16193288; http://dx.doi.org/10.1007/s00125-005-1951-8
10. Cébe-Suarez S, Grünewald FS, Jaussi R, Li X, Claesson-Welsh L, Spillmann D, et al. Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR. FASEB J 2008; 22:3078-86; PMID:18467594; http://dx.doi.org/10.1096/fj.08-107219
11. Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 2008; 8:880-7; PMID:18923433; http://dx.doi.org/10. 1038/nrc2505
12. Bevan HS, van den Akker NM, Qiu Y, Polman JA, Foster RR, Yem J, et al. The alternatively spliced anti-angiogenic family of VEGF isoforms VEGFxxxb in human kidney development. Nephron, Physiol 2008; 110:57-67; http://dx.doi.org/ 10.1159/000177614
13. Woolard J, Bevan HS, Harper SJ, Bates DO. Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation 2009; 16:572-92; PMID:19521900; http://dx.doi.org/10.1080/10739680902997333
14. Ribeiro LA, Bacci ML, Seren E, Tamanini C, Forni M. Characterization and differential expression of vascular endothelial growth factor isoforms and receptors in swine corpus luteum throughout estrous cycle. Mol Reprod Dev 2007; 74:163-71; PMID:16967516; http://dx.doi.org/10.1002/mrd.20589
15. Xu J, Dou T, Liu C, Fu M, Huang Y, Gu S, et al. The evolution of alternative splicing exons in vascular endothelial growth factor A. Gene 2011; 487:143-50; PMID:21782909; http://dx.doi.org/10.1016/j.gene.2011.06.024
16. Artac RA, McFee RM, Smith RA, Baltes-Breitwisch MM, Clopton DT, Cupp AS. Neutralization of vascular endothelial growth factor antiangiogenic isoforms is more effective than treatment with proangiogenic isoforms in stimulating vascular development and follicle progression in the perinatal rat ovary. Biol Reprod 2009; 81:978-88; PMID:19605786; http://dx.doi.org/10.1095/biolreprod.109. 078097
17. Ergorul C, Ray A, Huang W, Darland D, Luo ZK, Grosskreutz CL. Levels of vascular endothelial growth factor-A165b (VEGF-A165b) are elevated in experimental glaucoma. Mol Vis 2008; 14:1517-24; PMID:18728749
18. Kawamura H, Li X, Harper SJ, Bates DO, Claesson-Welsh L. Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res 2008; 68:4683-92; PMID:18559514; http://dx.doi.org/10.1158/ 0008-5472.CAN-07-6577
19. 165b are weakly angiogenic isoforms of VEGF-A. Mol Cancer 2010; 9:320; PMID:21194429; http://dx.doi.org/10.1186/1476- 4598-9-320
20. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007; 14:185-93; PMID:17310252; http://dx.doi.org/10.1038/nsmb1209
21. Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G, et al. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem 2010; 285:5532-40; PMID:19906640; http://dx.doi.org/ 10.1074/jbc.M109.074930
22. Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, et al. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 2008; 121:3487-95; PMID:18843117; http://dx.doi.org/10.1242/jcs.016410
23. Manetti M, Guiducci S, Romano E, Ceccarelli C, Bellando-Randone S, Conforti ML, et al. Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ Res 2011; 109:e14-26; PMID:21636803; http://dx.doi.org/10.1161/CIRCRESAHA.111.242057
24. Merdzhanova G, Gout S, Keramidas M, Edmond V, Coll JL, Brambilla C, et al. The transcription factor E2F1 and the SR protein SC35 control the ratio of proangiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo. Oncogene 2010; 29:5392-403; PMID:20639906; http://dx.doi.org/10.1038/onc.2010.281
25. Díaz R, Peña C, Silva J, Lorenzo Y, García V, García JM, et al. p73 Isoforms affect VEGF, VEGF165b and PEDF expression in human colorectal tumors: VEGF165b downregulation as a marker of poor prognosis. Int J Cancer 2008; 123:1060-7; PMID:18546269; http://dx.doi.org/10. 1002/ijc.23619
26. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401-10; PMID:12778130; http://dx.doi.org/10.1038/nrc1093
27. Pritchard-Jones RO, Dunn DB, Qiu Y, Varey AH, Orlando A, Rigby H, et al. Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 2007; 97:223-30; PMID:17595666; http://dx.doi.org/10.1038/ sj.bjc.6603839
28. Varey AH, Rennel ES, Qiu Y, Bevan HS, Perrin RM, Raffy S, et al. VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer 2008; 98:1366-79; PMID:18349829; http://dx.doi.org/10.1038/sj.bjc.6604308
29. Peiris-Pagès M, Harper SJ, Bates DO, Ramani P. Balance of pro- versus anti-angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth. J Pathol 2010; 222:138-47; PMID:20662003; http://dx.doi.org/10.1002/path.2746
30. Rennel ES, Hamdollah-Zadeh MA, Wheatley ER, Magnussen A, Schüler Y, Kelly SP, et al. Recombinant human VEGF165b protein is an effective anti-cancer agent in mice. Eur J Cancer 2008; 44:1883-94; PMID:18657413; http://dx.doi.org/10.1016/j.ejca.2008.05.027
31. Rennel E, Waine E, Guan H, Schüler Y, Leenders W, Woolard J, et al. The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br J Cancer 2008; 98:1250-7; PMID:18349828; http://dx.doi.org/ 10.1038/sj.bjc.6604309
32. Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI, et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 2011; 20:768-80; PMID:22172722; http://dx.doi.org/10. 1016/j.ccr.2011.10.016
33. Zhao M, Shi X, Liang J, Miao Y, Xie W, Zhang Y, et al. Expression of pro- and anti-angiogenic isoforms of VEGF in the mouse model of oxygen-induced retinopathy. Exp Eye Res 2011; 93:921-6; PMID:22067127; http://dx.doi.org/10. 1016/j.exer.2011.10.013
34. Konopatskaya O, Churchill AJ, Harper SJ, Bates DO, Gardiner TA. VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice. Mol Vis 2006; 12:626-32; PMID:16735996
35. Magnussen AL, Rennel ES, Hua J, Bevan HS, Beazley Long N, Lehrling C, et al. VEGF-A165b is cytoprotective and antiangiogenic in the retina. Invest Ophthalmol Vis Sci 2010; 51:4273-81; PMID:20237249; http://dx.doi.org/10.1167/ iovs.09-4296
36. Ehlken C, Rennel ES, Michels D, Grundel B, Pielen A, Junker B, et al. Levels of VEGF but not VEGF(165b) are increased in the vitreous of patients with retinal vein occlusion. Am J Ophthalmol 2011; 152:298-303, e1; PMID:21621189; http://dx.doi.org/10.1016/j.ajo.2011.01.040
37. Hua J, Spee C, Kase S, Rennel ES, Magnussen AL, Qiu Y, et al. Recombinant human VEGF165b inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 2010; 51:4282-8; PMID:20237252; http://dx.doi.org/10.1167/ iovs.09-4360
38. Ricker LJ, Kijlstra A, Kessels AG, de Jager W, Liem AT, Hendrikse F, et al. Interleukin and growth factor levels in subretinal fluid in rhegmatogenous retinal detachment: a case-control study. PLoS One 2011; 6:e19141; PMID:21556354; http://dx.doi.org/10.1371/journal.pone.0019141
39. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003; 111:707-16; PMID:12618525
40. Ferguson J, Qiu Y, Sage LM, Neal CR, Bates DO, Harper SJ, et al. Ultrafiltration co-efficient in isolated intact glomeruli from podocyte-specific VEGF165b over-expressing transgenic mice. Microcirculation 14, 643 (Abstract) 2007.
41. Qiu Y, Ferguson J, Oltean S, Neal CR, Kaura A, Bevan H, et al. Overexpression of VEGF165b in podocytes reduces glomerular permeability. J Am Soc Nephrol 2010; 21:1498-509; PMID:20688932; http://dx.doi.org/10.1681/ASN. 2009060617
42. Oltean S, Neal CR, Mavrou A, Patel P, Ahad T, Alsop C, et al. VEGF165b overexpression restores normal glomerular water permeability in VEGF164-overexpressing adult mice. Am J Physiol Renal Physiol 2012; 303:F1026-36; PMID:22811490; http://dx.doi.org/10.1152/ajprenal.00410.2011
43. Schumacher VA, Jeruschke S, Eitner F, Becker JU, Pitschke G, Ince Y, et al. Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome. J Am Soc Nephrol 2007; 18:719-29; PMID:17267748; http://dx.doi.org/10.1681/ASN. 2006020124
44. Reddy JC, Morris JC, Wang J, English MA, Haber DA, Shi Y, et al. WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins. J Biol Chem 1995; 270:10878-84; PMID:7738027; http://dx.doi.org/10. 1074/jbc.270.18.10878
45. Qiu Y, Bevan H, Weeraperuma S, Wratting D, Murphy D, Neal CR, et al. Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF165b. FASEB J 2008; 22:1104-12; PMID:18032632; http://dx.doi.org/10.1096/fj.07-9718com
46. Bates DO, MacMillan PP, Manjaly JG, Qiu Y, Hudson SJ, Bevan HS, et al. The endogenous anti-angiogenic family of splice variants of VEGF, VEGFxxxb, are down-regulated in pre-eclamptic placentae at term. Clin Sci (Lond) 2006; 110:575-85; PMID:16451124; http://dx.doi.org/10.1042/CS20050292
47. 165b splice variant in pre-eclampsia. BJOG 2011; 118:1253-61; PMID:21668772; http://dx.doi.org/10.1111/j.1471-0528.2011.02925.x
48. Bills VL, Varet J, Millar A, Harper SJ, Soothill PW, Bates DO. Failure to up-regulate VEGF165b in maternal plasma is a first trimester predictive marker for pre-eclampsia. Clin Sci (Lond) 2009; 116:265-72; PMID:18826376; http://dx.doi.org/10.1042/CS20080270
49. LeRoy EC. Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am 1996; 22:675-94; PMID: 8923590; http://dx.doi.org/10.1016/S0889- 857X(05)70295-7
50. Manetti M, Guiducci S, Ibba-Manneschi L, Matucci-Cerinic M. Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis. J Cell Mol Med 2010; 14(6A):1241-54; PMID:20132409; http://dx.doi.org/10.1111/j.1582-4934.2010.01027.x
51. Simpson A, Custovic A, Tepper R, Graves P, Stern DA, Jones M, et al. Genetic variation in vascular endothelial growth factor-a and lung function. Am J Respir Crit Care Med 2012; 185:1197-204; PMID:22461367; http://dx.doi.org/10. 1164/rccm.201112-2191OC
52. Harris S, Craze M, Newton J, Fisher M, Shima DT, Tozer GM, et al. Do anti-angiogenic VEGF (VEGFxxxb) isoforms exist? A cautionary tale. PLoS One 2012; 7:e35231; PMID:22567098; http://dx.doi.org/10.1371/journal.pone.0035231
53. Qiu Y, Hoareau-Aveilla C, Oltean S, Harper SJ, Bates DO. The anti-angiogenic isoforms of VEGF in health and disease. Biochem Soc Trans 2009; 37:1207-13; PMID:19909248; http://dx.doi.org/10.1042/BST0371207
54. Baba T, McLeod DS, Edwards MM, Merges C, Sen T, Sinha D, et al. VEGF 165 b in the developing vasculatures of the fetal human eye. Dev Dyn 2012; 241:595-607; PMID:22275161; http://dx.doi.org/10.1002/dvdy.23743
55. Lipinski DM, Singh MS, MacLaren RE. Assessment of cone survival in response to CNTF, GDNF, and VEGF165b in a novel ex vivo model of end-stage retinitis pigmentosa. Invest Ophthalmol Vis Sci 2011; 52:7340-6; PMID:21873685; http://dx.doi.org/10.1167/iovs.11-7996
56. Glass CA, Harper SJ, Bates DO. The anti-angiogenic VEGF isoform VEGF165b transiently increases hydraulic conductivity, probably through VEGF receptor 1 in vivo. J Physiol 2006; 572:243-57; PMID:16423853
57. Bates DO, Hillman NJ, Williams B, Neal CR, Pocock TM. Regulation of microvascular permeability by vascular endothelial growth factors. J Anat 2002; 200:581-97; PMID:12162726; http://dx.doi.org/10.1046/j.1469-7580.2002.00066.x
58. Baltes-Breitwisch MM, Artac RA, Bott RC, McFee RM, Kerl JG, Clopton DT, et al. Neutralization of vascular endothelial growth factor antiangiogenic isoforms or administration of proangiogenic isoforms stimulates vascular development in the rat testis. Reproduction 2010; 140:319-29; PMID:20457593; http://dx.doi.org/10.1530/REP-09-0456