The Yin and Yang of VEGF and PEDF: Multifaceted neurotrophic factors and their potential in the treatment of Parkinson's disease

International Journal of Molecular Sciences

Volumn 11, Issue 8, 2010, Pages 2875-2900

  Falk, Torsten ^a   Gonzalez, Robert T ^a   Sherman, Scott J ^a  

^a UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

Author keywords

Neurodegeneration; PEDF; PEDF R; VEGF A; VEGF B; VEGFR1; VEGFR2

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; EPIDERMAL GROWTH FACTOR; FIBROBLAST GROWTH FACTOR 2; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; ISOPROTEIN; NEUROTROPHIC FACTOR; NEURTURIN; PIGMENT EPITHELIUM DERIVED FACTOR; VASCULOTROPIN; VASCULOTROPIN A; VASCULOTROPIN B; VASCULOTROPIN RECEPTOR 1; EYE PROTEIN; NERVE GROWTH FACTOR; PIGMENT EPITHELIUM-DERIVED FACTOR; SERINE PROTEINASE INHIBITOR;

AMYOTROPHIC LATERAL SCLEROSIS; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; BRAIN EDEMA; CELL TRANSPLANTATION; CLINICAL TRIAL; CONTINUOUS INFUSION; DEGENERATIVE DISEASE; DOPAMINERGIC NERVE CELL; DRUG DOSE COMPARISON; DRUG HALF LIFE; DRUG MECHANISM; DRUG MEGADOSE; HUMAN; INTRACELLULAR SIGNALING; LOW DRUG DOSE; NERVE DEGENERATION; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PATHOPHYSIOLOGY; PIGMENT EPITHELIUM; PLEIOTROPY; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SYMPTOMATOLOGY; GENE THERAPY; GENETICS; METABOLISM;

EYE PROTEINS; GENETIC THERAPY; HUMANS; NERVE GROWTH FACTORS; PARKINSON DISEASE; SERPINS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 77957928091     PISSN: None     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms11082875     Document Type: Review

References (133)

1. Rezak, M. Current pharmacotherapeutic treatment options in Parkinson's disease. Disease-a- Month 2007, 53, 214-222.
2. Olanow, C.W.; Stern, M.B.; Sethi, K. The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology 2009, 72, S1-S136.
3. Nutt, J.G. Motor fluctuations and dyskinesia in Parkinson's disease. Parkinsonism Relat. Disord. 2001, 8, 101-108.
4. Forno, L.S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 1996, 55, 259-272.
5. Fahn, S.; Sulzer, D. Neurodegeneration and neuroprotection in Parkinson disease. NeuroRx 2004, 1, 139-154.
6. Fernandez-Espejo, E. Pathogenesis of Parkinson's disease: Prospects of neuroprotective and restorative therapies. Mol. Neurobiol. 2004, 29, 15-30.
7. Farrer, M.J. Genetics of Parkinson disease: Paradigm shifts and future prospects. Nat. Rev. Genet. 2006, 7, 306-318.
8. Jankovic, J. Parkinson's disease: Clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 2008, 79, 368-376.
9. Drucker-Colin, R.; Verdugo-Diaz, L. Cell transplantation for Parkinson's disease: Present status. Cell Mol. Neurobiol. 2004, 24, 301-316.
10. Kordower, J.H. In vivo gene delivery of glial cell line--derived neurotrophic factor for Parkinson's disease. Ann. Neurol. 2003, 53, S120-S132; discussion S132-S134.
11. Lindvall, O.; Bjorklund, A. Cell therapy in Parkinson's disease. NeuroRx 2004, 1, 382-393.
12. Olanow, C.W.; Goetz, C.G.; Kordower, J.H.; Stoessl, A.J.; Sossi, V.; Brin, M.F.; Shannon, K. M.; Nauert, G.M.; Perl, D P.; Godbold, J.; Freeman, T.B. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann. Neurol. 2003, 54, 403-414.
13. Kordower, J.H.; Chu, Y.; Hauser, R.A.; Freeman, T.B.; Olanow, C.W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat. Med. 2008, 14, 504-506.
14. Li, J.Y.; Englund, E.; Holton, J.L.; Soulet, D.; Hagell, P.; Lees, A.J.; Lashley, T.; Quinn, N.P.; Rehncrona, S.; Bjorklund, A.; Widner, H.; Revesz, T.; Lindvall, O.; Brundin, P. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 2008, 14, 501-503.
15. Mendez, I.; Vinuela, A.; Astradsson, A.; Mukhida, K.; Hallett, P.; Robertson, H.; Tierney, T.; Holness, R.; Dagher, A.; Trojanowski, J.Q.; Isacson, O. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat. Med. 2008, 14, 507-509.
16. Kirik, D.; Georgievska, B.; Bjorklund, A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat. Neurosci. 2004, 7, 105-110.
17. Peterson, A.L.; Nutt, J.G. Treatment of Parkinson's disease with trophic factors. Neurotherapeutics 2008, 5, 270-280.
18. Grothe, C.; Timmer, M. The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system. Brain Res. Rev. 2007, 54, 80-91.
19. Eidelberg, D. Metabolic brain networks in neurodegenerative disorders: A functional imaging approach. Trends Neurosci. 2009, 32, 548-557.
20. Graeber, M.B. Biomarkers for Parkinson's disease. Exp. Neurol. 2009, 216, 249-253.
21. Maetzler, W.; Liepelt, I.; Berg, D. Progression of Parkinson's disease in the clinical phase: Potential markers. Lancet Neurol. 2009, 8, 1158-1171.
22. Senger, D.R.; Galli, S.J.; Dvorak, A.M.; Perruzzi, C.A.; Harvey, V.S.; Dvorak, H.F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983, 219, 983-985.
23. Ferrara, N.; Henzel, W.J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 1989, 161, 851-858.
24. Ferrara, N.; Gerber, H.P.; LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 2003, 9, 669-676.
25. Houck, K.A.; Ferrara, N.; Winer, J.; Cachianes, G.; Li, B.; Leung, D.W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol. 1991, 5, 1806-1814.
26. Baldwin, M.E.; Roufail, S.; Halford, M.M.; Alitalo, K.; Stacker, S.A.; Achen, M.G. Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis. J. Biol. Chem. 2001, 276, 44307-44314.
27. Houck, K.A.; Leung, D.W.; Rowland, A.M.; Winer, J.; Ferrara, N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J. Biol. Chem. 1992, 267, 26031-26037.
28. Keyt, B.A.; Berleau, L.T.; Nguyen, H.V.; Chen, H.; Heinsohn, H.; Vandlen, R.; Ferrara, N. The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency. J. Biol. Chem. 1996, 271, 7788-7795.
29. Soker, S.; Fidder, H.; Neufeld, G.; Klagsbrun, M. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain. J. Biol. Chem. 1996, 271, 5761-5767.
30. Shibuya, M.; Yamaguchi, S.; Yamane, A.; Ikeda, T.; Tojo, A.; Matsushime, H.; Sato, M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 1990, 5, 519-524.
31. Terman, B.I.; Carrion, M.E.; Kovacs, E.; Rasmussen, B.A.; Eddy, R.L.; Shows, T.B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 1991, 6, 1677-1683.
32. de Vries, C.; Escobedo, J.A.; Ueno, H.; Houck, K.; Ferrara, N.; Williams, L.T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992, 255, 989-991.
33. Davis-Smyth, T.; Chen, H.; Park, J.; Presta, L.G.; Ferrara, N. The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade. EMBO J. 1996, 15, 4919-4927.
34. Terman, B.I.; Dougher-Vermazen, M.; Carrion, M.E.; Dimitrov, D.; Armellino, D.C.; Gospodarowicz, D.; Bohlen, P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun. 1992, 187, 1579-1586.
35. Hiratsuka, S.; Minowa, O.; Kuno, J.; Noda, T.; Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl. Acad. Sci. USA 1998, 95, 9349-9354.
36. Olsson, A.K.; Dimberg, A.; Kreuger, J.; Claesson-Welsh, L. VEGF receptor signalling - in control of vascular function. Nat. Rev. Mol. Cell Biol. 2006, 7, 359-371.
37. Neufeld, G.; Cohen, T.; Shraga, N.; Lange, T.; Kessler, O.; Herzog, Y. The neuropilins: Multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 2002, 12, 13-19.
38. Soker, S.; Takashima, S.; Miao, H.Q.; Neufeld, G.; Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998, 92, 735-745.
39. Ferrara, N.; Carver-Moore, K.; Chen, H.; Dowd, M.; Lu, L.; O'Shea, K.S.; Powell-Braxton, L.; Hillan, K.J.; Moore, M.W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996, 380, 439-442.
40. Carmeliet, P.; Ferreira, V.; Breier, G.; Pollefeyt, S.; Kieckens, L.; Gertsenstein, M.; Fahrig, M.; Vandenhoeck, A.; Harpal, K.; Eberhardt, C.; Declercq, C.; Pawling, J.; Moons, L.; Collen, D.; Risau, W.; Nagy, A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996, 380, 435-439.
41. Shalaby, F.; Rossant, J.; Yamaguchi, T.P.; Gertsenstein, M.; Wu, X.F.; Breitman, M.L.; Schuh, A.C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995, 376, 62-66.
42. Gerber, H.P. VEGF is required for growth and survival in neonatal mice. Development 1998, 126, 1149-1159.
43. Gerber, H.P.; Malik, A.K.; Solar, G.P.; Sherman, D.; Liang, X.H.; Meng, G.; Hong, K.; Marsters, J.C.; Ferrara, N. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002, 417, 954-958.
44. Zelzer, E.; Mamluk, R.; Ferrara, N.; Johnson, R.S.; Schipani, E.; Olsen, B.R. VEGFA is necessary for chondrocyte survival during bone development. Development 2004, 131, 2161-2171.
45. Inai, T.; Mancuso, M.; Hashizume, H.; Baffert, F.; Haskell, A.; Baluk, P.; Hu-Lowe, D.D.; Shalinsky, D.R.; Thurston, G.; Yancopoulos, G.D.; McDonald, D.M. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 2004, 165, 35-52.
46. Jain, R.K. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat. Med. 2001, 7, 987-989.
47. Kamba, T.; Tam, B.Y.; Hashizume, H.; Haskell, A.; Sennino, B.; Mancuso, M.R.; Norberg, S.M.; O'Brien, S.M.; Davis, R.B.; Gowen, L.C.; Anderson, K.D.; Thurston, G.; Joho, S.; Springer, M.L.; Kuo, C.J.; McDonald, D.M. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am. J. Physiol. Heart Circ. Physiol. 2006, 290, H560-H576.
48. Bicknell, R.; Harris, A.L. Anticancer strategies involving the vasculature: Vascular targeting and the inhibition of angiogenesis. Semin Cancer Biol. 1992, 3, 399-407.
49. Augustin, H.G. Antiangiogenic tumour therapy: Will it work? Trends Pharmacol Sci. 1998, 19, 216-222.
50. Ho, Q.T.; Kuo, C.J. Vascular endothelial growth factor: Biology and therapeutic applications. Int. J. Biochem. Cell Biol. 2007, 39, 1349-1357.
51. Zhang, F.; Tang, Z.; Hou, X.; Lennartsson, J.; Li, Y.; Koch, A.W.; Scotney, P.; Lee, C.; Arjunan, P.; Dong, L.; Kumar, A.; Rissanen, T.T.; Wang, B.; Nagai, N.; Fons, P.; Fariss, R.; Zhang, Y.; Wawrousek, E.; Tansey, G.; Raber, J.; Fong, G.H.; Ding, H.; Greenberg, D.A.; Becker, K.G.; Herbert, J.M.; Nash, A.; Yla-Herttuala, S.; Cao, Y.; Watts, R.J.; Li, X. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc. Natl. Acad. Sci. USA 2009, 106, 6152-6157.
52. Casella, I.; Feccia, T.; Chelucci, C.; Samoggia, P.; Castelli, G.; Guerriero, R.; Parolini, I.; Petrucci, E.; Pelosi, E.; Morsilli, O.; Gabbianelli, M.; Testa, U.; Peschle, C. Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood 2003, 101, 1316-1323.
53. Jin, K.; Zhu, Y.; Sun, Y.; Mao, X.O.; Xie, L.; Greenberg, D.A. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2002, 99, 11946-11950.
54. Sun, Y.; Jin, K.; Childs, J.T.; Xie, L.; Mao, X.O.; Greenberg, D.A. Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: Evidence from knockout mice and growth factor administration. Dev. Biol. 2006, 289, 329-335.
55. Belgore, F.; Blann, A.; Neil, D.; Ahmed, A.S.; Lip, G.Y. Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries. J. Clin. Pathol. 2004, 57, 266-272.
56. Hedman, M.; Muona, K.; Hedman, A.; Kivela, A.; Syvanne, M.; Eranen, J.; Rantala, A.; Stjernvall, J.; Nieminen, M.S.; Hartikainen, J.; Yla-Herttuala, S. Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer. Gene Ther. 2009, 16, 629-634.
57. Dvorak, H.F.; Brown, L.F.; Detmar, M.; Dvorak, A.M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 1995, 146, 1029-1039.
58. Berger, D.P.; Herbstritt, L.; Dengler, W.A.; Marme, D.; Mertelsmann, R.; Fiebig, H.H. Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies. Ann. Oncol. 1995, 6, 817-825.
59. Wood, J.M.; Bold, G.; Buchdunger, E.; Cozens, R.; Ferrari, S.; Frei, J.; Hofmann, F.; Mestan, J.; Mett, H.; O'Reilly, T.; Persohn, E.; Rosel, J.; Schnell, C.; Stover, D.; Theuer, A.; Towbin, H.; Wenger, F.; Woods-Cook, K.; Menrad, A.; Siemeister, G.; Schirner, M.; Thierauch, K.H.; Schneider, M.R.; Drevs, J.; Martiny-Baron, G.; Totzke, F. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000, 60, 2178-2189.
60. Holash, J.; Davis, S.; Papadopoulos, N.; Croll, S.D.; Ho, L.; Russell, M.; Boland, P.; Leidich, R.; Hylton, D.; Burova, E.; Ioffe, E.; Huang, T.; Radziejewski, C.; Bailey, K.; Fandl, J.P.; Daly, T.; Wiegand, S.J.; Yancopoulos, G.D.; Rudge, J.S. VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. USA 2002, 99, 11393-11398.
61. Herbst, R.S. Therapeutic options to target angiogenesis in human malignancies. Expert Opin. Emerg. Drugs 2006, 11, 635-650.
62. Boer, K.; Troost, D.; Spliet, W.G.; van Rijen, P.C.; Gorter, J.A.; Aronica, E. Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB. Acta Neuropathol. 2008, 115, 683-696.
63. Poesen, K.; Lambrechts, D.; Van Damme, P.; Dhondt, J.; Bender, F.; Frank, N.; Bogaert, E.; Claes, B.; Heylen, L.; Verheyen, A.; Raes, K.; Tjwa, M.; Eriksson, U.; Shibuya, M.; Nuydens, R.; Van Den Bosch, L.; Meert, T.; D'Hooge, R.; Sendtner, M.; Robberecht, W.; Carmeliet, P. Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration. J. Neurosci. 2008, 28, 10451-10459.
64. Wada, K.; Arai, H.; Takanashi, M.; Fukae, J.; Oizumi, H.; Yasuda, T.; Mizuno, Y.; Mochizuki, H. Expression levels of vascular endothelial growth factor and its receptors in Parkinson's disease. Neuroreport 2006, 17, 705-709.
65. Falk, T.; Zhang, S.; Sherman, S.J. Vascular endothelial growth factor B (VEGF-B) is upregulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease. Mol. Neurodegener 2009, 4, 49.
66. Ryu, J.K.; Cho, T.; Choi, H.B.; Wang, Y.T.; McLarnon, J.G. Microglial VEGF receptor response is an integral chemotactic component in Alzheimer's disease pathology. J. Neurosci. 2009, 29, 3-13.
67. Bogaert, E.; Van Damme, P.; Poesen, K.; Dhondt, J.; Hersmus, N.; Kiraly, D.; Scheveneels, W.; Robberecht, W.; van Den Bosch, L. VEGF protects motor neurons against excitotoxicity by upregulation of GluR2. Neurobiol. Aging 2009, doi:10.1016/j.neurobiolaging.2008.12.007.
68. Hoglinger, G.U.; Widmer, H.R.; Spenger, C.; Meyer, M.; Seiler, R.W.; Oertel, W.H.; Sautter, J. Influence of time in culture and BDNF pretreatment on survival and function of grafted embryonic rat ventral mesencephalon in the 6-OHDA rat model of Parkinson's disease. Exp. Neurol. 2001, 167, 148-157.
69. Lin, L.F.; Doherty, D.H.; Lile, J.D.; Bektesh, S.; Collins, F. GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993, 260, 1130-1132.
70. Casper, D.; Roboz, G.J.; Blum, M. Epidermal growth factor and basic fibroblast growth factor have independent actions on mesencephalic dopamine neurons in culture. J. Neurochem. 1994, 62, 2166-2177.
71. Pitzer, M.R.; Sortwell, C.E.; Daley, B.F.; McGuire, S.O.; Marchionini, D.; Fleming, M.; Collier, T.J. Angiogenic and neurotrophic effects of vascular endothelial growth factor (VEGF165): Studies of grafted and cultured embryonic ventral mesencephalic cells. Exp. Neurol. 2003, 182, 435-445.
72. Silverman, W.F.; Krum, J.M.; Mani, N.; Rosenstein, J.M. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 1999, 90, 1529-1541.
73. Jin, K.L.; Mao, X.O.; Greenberg, D.A. Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia. Proc. Natl. Acad. Sci. USA 2000, 97, 10242-10247.
74. Yasuhara, T.; Shingo, T.; Kobayashi, K.; Takeuchi, A.; Yano, A.; Muraoka, K.; Matsui, T.; Miyoshi, Y.; Hamada, H.; Date, I. Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson's disease. Eur. J. Neurosci. 2004, 19, 1494-1504.
75. Yasuhara, T.; Shingo, T.; Muraoka, K.; Yuan, W.; Kameda, M.; Takeuchi, A.; Yano, A.; Nishio, S.; Matsui, T.; Miyoshi, Y.; Hamada, H.; Date, I. The differences between high and low-dose administration of VEGF to dopaminergic neurons of in vitro and in vivo Parkinson's disease model. Brain Res. 2005, 1038, 1-10.
76. Yasuhara, T.; Shingo, T.; Muraoka, K.; Kameda, M.; Agari, T.; Wen Ji, Y.; Hayase, H.; Hamada, H.; Borlongan, C.V.; Date, I. Neurorescue effects of VEGF on a rat model of Parkinson's disease. Brain Res. 2005, 1053, 10-18.
77. Barleon, B.; Sozzani, S.; Zhou, D.; Weich, H.A.; Mantovani, A.; Marme, D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996, 87, 3336-3343.
78. Harrigan, M.R.; Ennis, S.R.; Masada, T.; Keep, R.F. Intraventricular infusion of vascular endothelial growth factor promotes cerebral angiogenesis with minimal brain edema. Neurosurgery 2002, 50, 589-598.
79. Schoch, H.J.; Fischer, S.; Marti, H.H. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 2002, 125, 2549-2557.
80. Olofsson, B.; Pajusola, K.; von Euler, G.; Chilov, D.; Alitalo, K.; Eriksson, U. Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J. Biol. Chem. 1996, 271, 19310-19317.
81. Li, Y.; Zhang, F.; Nagai, N.; Tang, Z.; Zhang, S.; Scotney, P.; Lennartsson, J.; Zhu, C.; Qu, Y.; Fang, C.; Hua, J.; Matsuo, O.; Fong, G.H.; Ding, H.; Cao, Y.; Becker, K.G.; Nash, A.; Heldin, C.H.; Li, X. VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats. J. Clin. Invest. 2008, 118, 913-923.
82. Mould, A.W.; Greco, S.A.; Cahill, M.M.; Tonks, I.D.; Bellomo, D.; Patterson, C.; Zournazi, A.; Nash, A.; Scotney, P.; Hayward, N.K.; Kay, G.F. Transgenic overexpression of vascular endothelial growth factor-B isoforms by endothelial cells potentiates postnatal vessel growth in vivo and in vitro. Circ. Res. 2005, 97, e60-70.
83. Silvestre, J.S.; Tamarat, R.; Ebrahimian, T.G.; Le-Roux, A.; Clergue, M.; Emmanuel, F.; Duriez, M.; Schwartz, B.; Branellec, D.; Levy, B.I. Vascular endothelial growth factor-B promotes in vivo angiogenesis. Circ. Res. 2003, 93, 114-123.
84. Aase, K.; von Euler, G.; Li, X.; Ponten, A.; Thoren, P.; Cao, R.; Cao, Y.; Olofsson, B.; Gebre- Medhin, S.; Pekny, M.; Alitalo, K.; Betsholtz, C.; Eriksson, U. Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect. Circulation 2001, 104, 358-364.
85. Reichelt, M.; Shi, S.; Hayes, M.; Kay, G.; Batch, J.; Gole, G.A.; Browning, J. Vascular endothelial growth factor-B and retinal vascular development in the mouse. Clin. Exp. Ophthalmol. 2003, 31, 61-65.
86. Rissanen, T.T.; Markkanen, J.E.; Gruchala, M.; Heikura, T.; Puranen, A.; Kettunen, M.I.; Kholova, I.; Kauppinen, R.A.; Achen, M.G.; Stacker, S.A.; Alitalo, K.; Yla-Herttuala, S. VEGFD is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ. Res. 2003, 92, 1098-1106.
87. Yue, X.; Falk, T.; Zhang, S.; Sherman, S.J. Vascular endothelial growth factor-B-186 improves motor behavior in vivo in a rat model of Parkinson's disease. Mov. Disord. 2010, 25, S254.
88. Ek, E.T.; Dass, C.R.; Choong, P.F. PEDF: A potential molecular therapeutic target with multiple anti-cancer activities. Trends Mol. Med. 2006, 12, 497-502.
89. Tombran-Tink, J.; Chader, G.G.; Johnson, L.V. PEDF: A pigment epithelium-derived factor with potent neuronal differentiative activity. Exp. Eye Res. 1991, 53, 411-414.
90. Broadhead, M.L.; Dass, C.R.; Choong, P.F. Cancer cell apoptotic pathways mediated by PEDF: Prospects for therapy. Trends Mol. Med. 2009, 15, 461-467.
91. Tombran-Tink, J.; Johnson, L.V. Neuronal differentiation of retinoblastoma cells induced by medium conditioned by human RPE cells. Invest Ophthalmol. Vis. Sci. 1989, 30, 1700-1707.
92. Dawson, D.W.; Volpert, O.V.; Gillis, P.; Crawford, S.E.; Xu, H.; Benedict, W.; Bouck, N.P. Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. Science 1999, 285, 245-248.
93. Tombran-Tink, J.; Barnstable, C.J. PEDF: A multifaceted neurotrophic factor. Nat. Rev. Neurosci. 2003, 4, 628-636.
94. Sariola, H. The neurotrophic factors in non-neuronal tissues. Cell Mol. Life Sci. 2001, 58, 1061-1066.
95. Becerra, S.P. Structure-function studies on PEDF: A noninhibitory serpin with neurotrophic activity. Adv. Exp. Med. Biol. 1997, 425, 223-237.
96. Steele, F.R.; Chader, G.J.; Johnson, L.V.; Tombran-Tink, J. Pigment epithelium-derived factor: Neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc. Natl. Acad. Sci. USA 1993, 90, 1526-1530.
97. Tombran-Tink, J.; Mazuruk, K.; Rodriguez, I.R.; Chung, D.; Linker, T.; Englander, E.; Chader, G.J. Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium-derived factor, a unique neurotrophic serpin. Mol. Vis. 1996, 2, 11.
98. Becerra, S.P. Focus on Molecules: Pigment epithelium-derived factor (PEDF). Exp. Eye Res. 2006, 82, 739-740.
99. Alberdi, E.; Aymerich, M.S.; Becerra, S.P. Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons. Evidence for a PEDF receptor. J. Biol. Chem. 1999, 274, 31605-31612.
100. Kozaki, K.; Miyaishi, O.; Koiwai, O.; Yasui, Y.; Kashiwai, A.; Nishikawa, Y.; Shimizu, S.; Saga, S. Isolation, purification, and characterization of a collagen-associated serpin, caspin, produced by murine colon adenocarcinoma cells. J. Biol. Chem. 1998, 273, 15125-15130.
101. Meyer, C.; Notari, L.; Becerra, S.P. Mapping the type I collagen-binding site on pigment epithelium-derived factor. Implications for its antiangiogenic activity. J. Biol. Chem. 2002, 277, 45400-45407.
102. Bilak, M.M.; Becerra, S.P.; Vincent, A.M.; Moss, B.H.; Aymerich, M.S.; Kuncl, R.W. Identification of the neuroprotective molecular region of pigment epithelium-derived factor and its binding sites on motor neurons. J. Neurosci. 2002, 22, 9378-9386.
103. Filleur, S.; Volz, K.; Nelius, T.; Mirochnik, Y.; Huang, H.; Zaichuk, T.A.; Aymerich, M.S.; Becerra, S.P.; Yap, R.; Veliceasa, D.; Shroff, E.H.; Volpert, O.V. Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. Cancer Res. 2005, 65, 5144-5152.
104. Hosomichi, J.; Yasui, N.; Koide, T.; Soma, K.; Morita, I. Involvement of the collagen I-binding motif in the anti-angiogenic activity of pigment epithelium-derived factor. Biochem. Biophys. Res. Commun. 2005, 335, 756-761.
105. Notari, L.; Baladron, V.; Aroca-Aguilar, J.D.; Balko, N.; Heredia, R.; Meyer, C.; Notario, P.M.; Saravanamuthu, S.; Nueda, M.L.; Sanchez-Sanchez, F.; Escribano, J.; Laborda, J.; Becerra, S.P. Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J. Biol. Chem. 2006, 281, 38022-38037.
106. Ho, T.C.; Chen, S.L.; Yang, Y.C.; Lo, T.H.; Hsieh, J.W.; Cheng, H.C.; Tsao, Y.P. Cytosolic phospholipase A2-{alpha} is an early apoptotic activator in PEDF-induced endothelial cell apoptosis. Am. J. Physiol. Cell Physiol. 2009, 296, C273-284.
107. Andreu-Agullo, C.; Morante-Redolat, J.M.; Delgado, A.C.; Farinas, I. Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone. Nat. Neurosci. 2009, 12, 1514-1523.
108. Volpert, O.V.; Zaichuk, T.; Zhou, W.; Reiher, F.; Ferguson, T.A.; Stuart, P.M.; Amin, M.; Bouck, N.P. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat. Med. 2002, 8, 349-357.
109. Ferreira, J.J.; Neutel, D.; Mestre, T.; Coelho, M.; Rosa, M.M.; Rascol, O.; Sampaio, C. Skin cancer and Parkinson's disease. Mov. Disord. 2010, 25, 139-148.
110. Orgaz, J.L.; Ladhani, O.; Hoek, K.S.; Fernandez-Barral, A.; Mihic, D.; Aguilera, O.; Seftor, E.A.; Bernad, A.; Rodriguez-Peralto, J.L.; Hendrix, M.J.; Volpert, O.V.; Jimenez, B. 'Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma'. Oncogene 2009, 28, 4147-4161.
111. Sasaki, Y.; Naishiro, Y.; Oshima, Y.; Imai, K.; Nakamura, Y.; Tokino, T. Identification of pigment epithelium-derived factor as a direct target of the p53 family member genes. Oncogene 2005, 24, 5131-5136.
112. Gao, G.; Li, Y.; Zhang, D.; Gee, S.; Crosson, C.; Ma, J. Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett. 2001, 489, 270-276.
113. Ohno-Matsui, K.; Morita, I.; Tombran-Tink, J.; Mrazek, D.; Onodera, M.; Uetama, T.; Hayano, M.; Murota, S.I.; Mochizuki, M. Novel mechanism for age-related macular degeneration: An equilibrium shift between the angiogenesis factors VEGF and PEDF. J. Cell Physiol. 2001, 189, 323-333.
114. Funatsu, H.; Yamashita, H.; Nakamura, S.; Mimura, T.; Eguchi, S.; Noma, H.; Hori, S. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 2006, 113, 294-301.
115. Bilak, M.M.; Corse, A.M.; Bilak, S.R.; Lehar, M.; Tombran-Tink, J.; Kuncl, R.W. Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J. Neuropathol. Exp. Neurol. 1999, 58, 719-728.
116. DeCoster, M.A.; Schabelman, E.; Tombran-Tink, J.; Bazan, N.G. Neuroprotection by pigment epithelial-derived factor against glutamate toxicity in developing primary hippocampal neurons. J. Neurosci. Res. 1999, 56, 604-610.
117. Taniwaki, T.; Hirashima, N.; Becerra, S.P.; Chader, G.J.; Etcheberrigaray, R.; Schwartz, J.P. Pigment epithelium-derived factor protects cultured cerebellar granule cells against glutamateinduced neurotoxicity. J. Neurochem. 1997, 68, 26-32.
118. Taniwaki, T.; Becerra, S.P.; Chader, G.J.; Schwartz, J.P. Pigment epithelium-derived factor is a survival factor for cerebellar granule cells in culture. J. Neurochem. 1995, 64, 2509-2517.
119. Houenou, L.J.; D'Costa, A.P.; Li, L.; Turgeon, V.L.; Enyadike, C.; Alberdi, E.; Becerra, S.P. Pigment epithelium-derived factor promotes the survival and differentiation of developing spinal motor neurons. J. Comp. Neurol. 1999, 412, 506-514.
120. Crawford, S.E.; Stellmach, V.; Ranalli, M.; Huang, X.; Huang, L.; Volpert, O.; De Vries, G.H.; Abramson, L.P.; Bouck, N. Pigment epithelium-derived factor (PEDF) in neuroblastoma: A multifunctional mediator of Schwann cell antitumor activity. J. Cell Sci. 2001, 114, 4421-4428.
121. Kuncl, R.W.; Bilak, M.M.; Bilak, S.R.; Corse, A.M.; Royal, W.; Becerra, S.P. Pigment epithelium-derived factor is elevated in CSF of patients with amyotrophic lateral sclerosis. J. Neurochem. 2002, 81, 178-184.
122. McKay, B.S.; Goodman, B.; Falk, T.; Sherman, S.J. Retinal pigment epithelial cell transplantation could provide trophic support in Parkinson's disease: Results from an in vitro model system. Exp. Neurol. 2006, 201, 234-243.
123. Watts, R.L.; Raiser, C.D.; Stover, N.P.; Cornfeldt, M.L.; Schweikert, A.W.; Allen, R.C.; Subramanian, T.; Doudet, D.; Honey, C.R.; Bakay, R.A. Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: A potential new cell therapy for Parkinson's disease. J. Neural. Transm. Suppl. 2003, 65, 215-227.
124. Ming, M.; Li, X.; Fan, X.; Yang, D.; Li, L.; Chen, S.; Gu, Q.; Le, W. Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: Possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease. J. Transl. Med. 2009, 7, 53.
125. Falk, T.; Zhang, S.; Sherman, S.J. Pigment epithelium derived factor (PEDF) is neuroprotective in two in vitro models of Parkinson's disease. Neurosci. Lett. 2009, 458, 49-52.
126. Watts, R.L.; Gross, R.E.; Hauser, R.A.; Bakay, R.A.E.; Reichmann, H.; Weisner, N.P.; Stover, D.; Reissig, E.; Steiner-Schulze, H.; Fichte, K. The STEPS trial: A phase 2b study evaluating Spheramine® in patients with advanced Parkinson's disease. Mov. Disord. 2009, 24, LB-18.
127. Ogata, N.; Nishikawa, M.; Nishimura, T.; Mitsuma, Y.; Matsumura, M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am. J. Ophthalmol. 2002, 134, 348-353.
128. Ohno-Matsui, K.; Yoshida, T.; Uetama, T.; Mochizuki, M.; Morita, I. Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells. Biochem. Biophys. Res. Commun. 2003, 303, 962-967.
129. Angayarkanni, N.; Selvi, R.; Pukhraj, R.; Biswas, J.; Bhavesh, S.J.; Tombran-Tink, J. Ratio of the vitreous vascular endothelial growth factor and pigment epithelial-derived factor in Eales disease. J. Ocul. Biol. Dis. Infor. 2009, 2, 20-28.
130. Elayappan, B.; Ravinarayannan, H.; Sardar Pasha, S.P.; Lee, K.J.; Gurunathan, S. PEDF inhibits VEGF- and EPO- induced angiogenesis in retinal endothelial cells through interruption of PI3K/Akt phosphorylation. Angiogenesis 2009, 12, 313-324.
131. Notari, L.; Miller, A.; Martinez, A.; Amaral, J.; Ju, M.; Robinson, G.; Smith, L.E.; Becerra, S.P. Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: Implications for downregulation in hypoxia. Invest. Ophthalmol. Vis. Sci. 2005, 46, 2736-2747.
132. Zheng, Z.; Chen, H.; Zhao, H.; Liu, K.; Luo, D.; Chen, Y.; Chen, Y.; Yang, X.; Gu, Q.; Xu, X. Inhibition of JAK2/STAT3-mediated VEGF upregulation under high glucose conditions by PEDF through a mitochondrial ROS pathway in vitro. Invest. Ophthalmol. Vis. Sci. 2009, 51, 64-71.
133. Yasuda, T.; Fukuda-Tani, M.; Nihira, T.; Wada, K.; Hattori, N.; Mizuno, Y.; Mochizuki, H. Correlation between levels of pigment epithelium-derived factor and vascular endothelial growth factor in the striatum of patients with Parkinson's disease. Exp. Neurol. 2007, 206, 308-317.