Vascular endothelial growth factor: A neurovascular target in neurological diseases

Nature Reviews Neurology

Volumn 12, Issue 8, 2016, Pages 439-454

  Lange, Christian ^a   Storkebaum, Erik ^b,c   De Almodóvar, Carmen Ruiz ^d   Dewerchin, Mieke ^a   Carmeliet, Peter ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b MAX PLANCK INSTITUTE FOR MOLECULAR BIOMEDICINE   (Germany)

^c UNIVERSITY OF MÜNSTER   (Germany)

^d UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AFLIBERCEPT; AMYLOID BETA PROTEIN; BEVACIZUMAB; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; LENTIVIRUS VECTOR; NANOSPHERE; PARVOVIRUS VECTOR; PEGPLERANIB; RANIBIZUMAB; RAPAMYCIN; RECOMBINANT VASCULOTROPIN; VASCULOTROPIN; VASCULOTROPIN 165; VASCULOTROPIN B; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; RECOMBINANT PROTEIN; VASCULOTROPIN A; VEGFA PROTEIN, HUMAN;

AGE RELATED MACULAR DEGENERATION; ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; ANGIOGENESIS; BLOOD BRAIN BARRIER; BRAIN ISCHEMIA; BRAIN PERFUSION; DEMYELINATING DISEASE; DIABETIC MACULAR EDEMA; DIABETIC RETINOPATHY; EPILEPSY; EYE DISEASE; HUMAN; HUNTINGTON CHOREA; LIMB ISCHEMIA; LOW DRUG DOSE; MACULAR EDEMA; MESENCHYMAL STEM CELL; MYELOOPTIC NEUROPATHY; NEOVASCULAR AGE RELATED MACULAR DEGENERATION; NERVE REGENERATION; NERVOUS SYSTEM DEVELOPMENT; NEURAL STEM CELL; NEUROLOGIC DISEASE; NEUROPROTECTION; NON NEOVASCULAR AGE RELATED MACULAR DEGENERATION; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PERIPHERAL NERVE INJURY; PERIPHERAL NEUROPATHY; PRIORITY JOURNAL; REVIEW; TRAUMATIC BRAIN INJURY; ANIMAL; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL (TOPIC); DRUG DELIVERY SYSTEM; METABOLISM; PROCEDURES; TRENDS;

ANIMALS; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; HUMANS; NERVOUS SYSTEM DISEASES; RECOMBINANT PROTEINS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84976538547     PISSN: 17594758     EISSN: 17594766     Source Type: Journal    
DOI: 10.1038/nrneurol.2016.88     Document Type: Review

References (196)

1. Koch, S., & Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb. Perspect. Med. 2, a006502 (2012
2. Ruiz De Almodovar, C., Lambrechts, D., Mazzone, M., & Carmeliet, P. Role and therapeutic potential of VEGF in the nervous system. Physiol. Rev. 89, 607-648 (2009
3. London, N. R., & Gurgel, R. K. The role of vascular endothelial growth factor and vascular stability in diseases of the ear. Laryngoscope 124, E340-E346 (2014
4. Dewerchin, M., & Carmeliet, P. Placental growth factor in cancer. Expert Opin. Ther. Targets 18, 1339-1354 (2014
5. Chinot, O. L., & Reardon, D. A. The future of antiangiogenic treatment in glioblastoma. Curr. Opin. Neurol. 27, 675-682 (2014
6. Carmeliet, P., & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298-307 (2011
7. Moens, S., Goveia, J., Stapor, P. C., Cantelmo, A. R., & Carmeliet, P. The multifaceted activity of VEGF in angiogenesis -implications for therapy responses. Cytokine Growth Factor Rev. 25, 473-482 (2014
8. Ferrara, N., & Adamis, A. P. Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov. 15, 385-403 (2016
9. 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.146, 1029-1039 (1995
10. Licht, T., & Keshet, E. Delineating multiple functions of VEGF A in the adult brain. Cell. Mol. Life Sci. 70, 1727-1737 (2013
11. Krishnapati, L. S., & Ghaskadbi, S. Identification and characterization of VEGF and FGF from Hydra. Int. J. Dev. Biol. 57, 897-906 (2013
12. Mackenzie, F., & Ruhrberg, C. Diverse roles for VEGF A in the nervous system. Development 139, 1371-1380 (2012
13. Quaegebeur, A., Lange, C., & Carmeliet, P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron 71, 406-424 (2011
14. Hogan, K. A., Ambler, C. A., Chapman, D. L., & Bautch, V. L. The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development 131, 1503-1513 (2004
15. James, J. M., Gewolb, C., & Bautch, V. L. Neurovascular development uses VEGF A signaling to regulate blood vessel ingression into the neural tube. Development 136, 833-841 (2009
16. Haigh, J. J., et al. Cortical and retinal defects caused by dosage-dependent reductions in VEGF A paracrine signaling. Dev. Biol. 262, 225-241 (2003
17. Raab, S., et al. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb. Haemost. 91, 595-605 (2004
18. Licht, T., Dor-Wollman, T., Ben-Zvi, A., Rothe, G., & Keshet, E. Vessel maturation schedule determines vulnerability to neuronal injuries of prematurity. J. Clin. Invest. 125, 1319-1328 (2015
19. Clayton, J. A., Chalothorn, D., & Faber, J. E. Vascular endothelial growth factor A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ. Res. 103, 1027-1036 (2008
20. Lucitti, J. L., et al. Formation of the collateral circulation is regulated by vascular endothelial growth factor A and a disintegrin and metalloprotease family members 10 and 17. Circ. Res. 111, 1539-1550 (2012
21. Ruiz De Almodovar, C., et al. Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1. J. Neurosci. 30, 15052-15066 (2010
22. He, W., et al. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526, 710-714 (2015
23. Schwarz, Q., et al. Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev. 18, 2822-2834 (2004
24. Erskine, L., et al. VEGF signaling through neuropilin 1 guides commissural axon crossing at the optic chiasm. Neuron 70, 951-965 (2011
25. Ruiz De Almodovar, C., et al. VEGF mediates commissural axon chemoattraction through its receptor Flk1. Neuron 70, 966-978 (2011
26. Le Guelte, A., Dwyer, J., & Gavard, J. Jumping the barrier: VE cadherin, VEGF and other angiogenic modifiers in cancer. Biol. Cell 103, 593-605 (2011
27. Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064-1078 (2015
28. Robberecht, W., & Philips, T. The changing scene of amyotrophic lateral sclerosis. Nat. Rev. Neurosci. 14, 248-264 (2013
29. Peters, O. M., Ghasemi, M., & Brown, R. H. Jr Emerging mechanisms of molecular pathology in ALS. J. Clin. Invest. 125, 1767-1779 (2015
30. Ilieva, H., Polymenidou, M., & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761-772 (2009
31. Garbuzova-Davis, S., et al. Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398, 113-125 (2011
32. Oosthuyse, B., et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat. Genet. 28, 131-138 (2001
33. Lambrechts, D., et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat. Genet. 34, 383-394 (2003
34. Lambrechts, D., et al. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype. J. Med. Genet. 46, 840-846 (2009
35. Storkebaum, E., et al. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery. Circulation 122, 273-281 (2010
36. Sasaki, S. Alterations of the blood-spinal cord barrier in sporadic amyotrophic lateral sclerosis. Neuropathology 35, 518-528 (2015
37. Li, B., Xu, W., Luo, C., Gozal, D., & Liu, R. VEGF-induced activation of the PI3 K/Akt pathway reduces mutant SOD1 mediated motor neuron cell death. Brain Res. Mol. Brain Res. 111, 155-164 (2003
38. Van Den Bosch, L., et al. Effects of vascular endothelial growth factor (VEGF) on motor neuron degeneration. Neurobiol. Dis. 17, 21-28 (2004
39. Tolosa, L., Mir, M., Olmos, G., & Llado, J. Vascular endothelial growth factor protects motoneurons from serum deprivation-induced cell death through phosphatidylinositol 3 kinase-mediated p38 mitogen-activated protein kinase inhibition. Neuroscience 158, 1348-1355 (2009
40. Tolosa, L., Mir, M., Asensio, V. J., Olmos, G., & Llado, J. Vascular endothelial growth factor protects spinal cord motoneurons against glutamate-induced excitotoxicity via phosphatidylinositol 3 kinase. J. Neurochem. 105, 1080-1090 (2008
41. Bogaert, E., et al. VEGF protects motor neurons against excitotoxicity by upregulation of GluR2. Neurobiol. Aging 31, 2185-2191 (2010
42. Lunn, J. S., Sakowski, S. A., Kim, B., Rosenberg, A. A., & Feldman, E. L. Vascular endothelial growth factor prevents G93A SOD1 induced motor neuron degeneration. Dev. Neurobiol. 69, 871-884 (2009
43. Brockington, A., et al. Expression of vascular endothelial growth factor and its receptors in the central nervous system in amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 65, 26-36 (2006
44. Poesen, K., et al. Novel role for vascular endothelial growth factor (VEGF) receptor 1 and its ligand VEGF B in motor neuron degeneration. J. Neurosci. 28, 10451-10459 (2008
45. Storkebaum, E., et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat. Neurosci. 8, 85-92 (2005
46. Azzouz, M., et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429, 413-417 (2004
47. Wang, Y., et al. Vascular endothelial growth factor overexpression delays neurodegeneration and prolongs survival in amyotrophic lateral sclerosis mice. J. Neurosci. 27, 304-307 (2007
48. Hwang, D. H., et al. Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice. Gene Ther. 16, 1234-1244 (2009
49. Dodge, J. C., et al. AAV4 mediated expression of IGF 1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice. Mol. Ther. 18, 2075-2084 (2010
50. Kliem, M. A., et al. Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP TF) improves functional outcomes in SOD1 rats. Amyotroph. Lateral Scler. 12, 331-339 (2011
51. Krakora, D., et al. Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model. Mol. Ther. 21, 1602-1610 (2013
52. Tovar Y. Romo, L. B., Zepeda, A., & Tapia, R. Vascular endothelial growth factor prevents paralysis and motoneuron death in a rat model of excitotoxic spinal cord neurodegeneration. J. Neuropathol. Exp. Neurol. 66, 913-922 (2007
53. Dotti, C. G., & De Strooper, B. Alzheimer's dementia by circulation disorders: when trees hide the forest. Nat. Cell Biol. 11, 114-116 (2009
54. Di Marco, L. Y., et al. Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol. Dis. 82, 593-606 (2015
55. Raz, L., Knoefel, J., & Bhaskar, K. The neuropathology and cerebrovascular mechanisms of dementia. J. Cereb. Blood Flow Metab. 36, 172-186 (2016
56. Van Cauwenberghe, C., Van Broeckhoven, C., & Sleegers, K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 18, 421-430 (2016
57. Jefferies, W. A., et al. Adjusting the compass: new insights into the role of angiogenesis in Alzheimer's disease. Alzheimers Res. Ther. 5, 64 (2013
58. Kalaria, R. N., Akinyemi, R., & Ihara, M. Does vascular pathology contribute to Alzheimer changes? J. Neurol. Sci. 322, 141-147 (2012
59. Snyder, H. M., et al. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement. 11, 710-717 (2015
60. Religa, P., et al. VEGF significantly restores impaired memory behavior in Alzheimer's mice by improvement of vascular survival. Sci. Rep. 3, 2053 (2013
61. Patel, N. S., et al. Alzheimer's β amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR 2. J. Neurochem. 112, 66-76 (2010
62. Biron, K. E., Dickstein, D. L., Gopaul, R., & Jefferies, W. A. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease. PLoS ONE 6, e23789 (2011
63. Zhang, Z., Cai, P., Zhou, J., Liu, M., & Jiang, X. Effects of asiaticoside on human umbilical vein endothelial cell apoptosis induced by Aβ1-42. Int. J. Clin. Exp. Med. 8, 15828-15833 (2015
64. Donnini, S., et al. Aβ peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis. FASEB J. 24, 2385-2395 (2010
65. Solerte, S. B., et al. Decreased release of the angiogenic peptide vascular endothelial growth factor in Alzheimer?s disease: recovering effect with insulin and DHEA sulfate. Dement. Geriatr. Cogn. Disord. 19, 1-10 (2005
66. Mateo, I., et al. Low serum VEGF levels are associated with Alzheimer's disease. Acta Neurol. Scand. 116, 56-58 (2007
67. Huang, L., Jia, J., & Liu, R. Decreased serum levels of the angiogenic factors VEGF and TGF β1 in Alzheimer's disease and amnestic mild cognitive impairment. Neurosci. Lett. 550, 60-63 (2013
68. Muche, A., Bigl, M., Arendt, T., & Schliebs, R. Expression of vascular endothelial growth factor (VEGF) mRNA, VEGF receptor 2 (Flk 1) mRNA, and of VEGF co receptor neuropilin (Nrp)-1 mRNA in brain tissue of aging Tg2576 mice by in situ hybridization. Int. J. Dev. Neurosci. 43, 25-34 (2015
69. Meyer, E. P., Ulmann-Schuler, A., Staufenbiel, M., & Krucker, T. Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease. Proc. Natl Acad. Sci. USA 105, 3587-3592 (2008
70. Dayalu, P., & Albin, R. L. Huntington disease: pathogenesis and treatment. Neurol. Clin. 33, 101-114 (2015
71. Carroll, J. B., Bates, G. P., Steffan, J., Saft, C., & Tabrizi, S. J. Treating the whole body in Huntington's disease. Lancet Neurol. 14, 1135-1142 (2015
72. Herrn, E., et al. VEGF-releasing biodegradable nanospheres administered by craniotomy: a novel therapeutic approach in the APP/Ps1 mouse model of Alzheimer's disease. J. Control. Release 170, 111-119 (2013
73. Garcia, K. O., et al. Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of Alzheimer's disease. Front. Aging Neurosci. 6, 30 (2014
74. Hohman, T. J., Bell, S. P., & Jefferson, A. L. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease. JAMA Neurol. 72, 520-529 (2015
75. Cesca, F., et al. Evaluating the SERCA2 and VEGF mRNAs as potential molecular biomarkers of the onset and progression in Huntington's disease. PLoS ONE 10, e0125259 (2015
76. Emerich, D. F., Mooney, D. J., Storrie, H., Babu, R. S., & Kordower, J. H. Injectable hydrogels providing sustained delivery of vascular endothelial growth factor are neuroprotective in a rat model of Huntington's disease. Neurotox. Res. 17, 66-74 (2010
77. Ellison, S. M., et al. Dose-dependent neuroprotection of VEGF165 in Huntington's disease striatum. Mol. Ther. 21, 1862-1875 (2013
78. Aarli, J. A., Dua, T., Janca, A., & Muscetta, A. Neurological disorders. Public health challenges. World Health Organization http://www.who.int/mental-health/neurology/neurological-disorders-report-web.pdf (2006
79. Wada, K., et al. Expression levels of vascular endothelial growth factor and its receptors in Parkinson's disease. Neuroreport 17, 705-709 (2006
80. Cabezas, R., et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease. Front. Cell. Neurosci. 8, 211 (2014
81. Ohlin, K. E., et al. Vascular endothelial growth factor is upregulated by l-dopa in the parkinsonian brain: implications for the development of dyskinesia. Brain 134, 2339-2357 (2011
82. Kortekaas, R., et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176-179 (2005
83. Faucheux, B. A., Bonnet, A. M., Agid, Y., & Hirsch, E. C. Blood vessels change in the mesencephalon of patients with Parkinson's disease. Lancet 353, 981-982 (1999
84. Issidorides, M. R. Neuronal vascular relationships in the zona compacta of normal and parkinsonian substantia nigra. Brain Res. 25, 289-299 (1971
85. Guan, J., et al. Vascular degeneration in Parkinson's disease. Brain Pathol. 23, 154-164 (2013
86. Rektor, I., et al. Impairment of brain vessels may contribute to mortality in patients with Parkinson's disease. Mov. Disord. 27, 1169-1172 (2012
87. Tian, Y. Y., et al. Favorable effects of VEGF gene transfer on a rat model of Parkinson disease using adeno-associated viral vectors. Neurosci. Lett. 421, 239-244 (2007
88. Yasuhara, T., et al. Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson's disease. Eur. J. Neurosci. 19, 1494-1504 (2004
89. Yasuhara, T., et al. 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. 1038, 1-10 (2005
90. Yasuhara, T., et al. Neurorescue effects of VEGF on a rat model of Parkinson's disease. Brain Res. 1053, 10-18 (2005
91. Herran, E., et al. Increased antiparkinson efficacy of the combined administration of VEGF-and GDNF-loaded nanospheres in a partial lesion model of Parkinson?s disease. Int. J. Nanomed. 9, 2677-2687 (2014
92. Herran, E., et al. In vivo administration of VEGF-and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson's disease. Eur. J. Pharm. Biopharm. 85, 1183-1190 (2013
93. Requejo, C., et al. Topographical distribution of morphological changes in a partial model of Parkinson's disease -effects of nanoencapsulated neurotrophic factors administration. Mol. Neurobiol. 52, 846-858 (2015
94. Glavaski-Joksimovic, A., & Bohn, M. C. Mesenchymal stem cells and neuroregeneration in Parkinson's disease. Exp. Neurol. 247, 25-38 (2013
95. Xiong, N., et al. VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson's disease. Gene Ther. 18, 394-402 (2011
96. Yue, X., et al. Comparative study of the neurotrophic effects elicited by VEGF B and GDNF in preclinical in vivo models of Parkinson's disease. Neuroscience 258, 385-400 (2014
97. Falk, T., Zhang, S., & Sherman, S. J. Vascular endothelial growth factor B (VEGF B) is up regulated and exogenous VEGF B is neuroprotective in a culture model of Parkinson's disease. Mol. Neurodegener. 4, 49 (2009
98. Falk, T., et al. Vascular endothelial growth factor B is neuroprotective in an in vivo rat model of Parkinson's disease. Neurosci. Lett. 496, 43-47 (2011
99. Pienaar, I. S., et al. Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease. Neurobiol. Dis. 74, 392-405 (2015
100. Remple, M. S., et al. Subthalamic nucleus neuronal firing rate increases with Parkinson's disease progression. Mov. Disord. 26, 1657-1662 (2011
101. Shinko, A., et al. Spinal cord stimulation exerts neuroprotective effects against experimental Parkinson's disease. PLoS ONE 9, e101468 (2014
102. Sytze Van Dam, P., Cotter, M. A., Bravenboer, B., & Cameron, N. E. Pathogenesis of diabetic neuropathy: focus on neurovascular mechanisms. Eur. J. Pharmacol. 719, 180-186 (2013
103. Carozzi, V. A., Canta, A., & Chiorazzi, A. Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms? Neurosci. Lett. 596, 90-107 (2015
104. Giannini, C., & Dyck, P. J. Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity. Ann. Neurol. 37, 498-504 (1995
105. Shimizu, F., Sano, Y., Haruki, H., & Kanda, T. Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood-nerve barrier by stimulating the release of TGF β and vascular endothelial growth factor (VEGF) by pericytes. Diabetologia 54, 1517-1526 (2011
106. Dyck, P. J., & Giannini, C. Pathologic alterations in the diabetic neuropathies of humans: a review. J. Neuropathol. Exp. Neurol. 55, 1181-1193 (1996
107. Schratzberger, P., et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J. Clin. Invest. 107, 1083-1092 (2001
108. Kirchmair, R., et al. Therapeutic angiogenesis inhibits or rescues chemotherapy-induced peripheral neuropathy: taxol-and thalidomide-induced injury of vasa nervorum is ameliorated by VEGF. Mol. Ther. 15, 69-75 (2007
109. Kirchmair, R., et al. Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. Circulation 111, 2662-2670 (2005
110. Samii, A., Unger, J., & Lange, W. Vascular endothelial growth factor expression in peripheral nerves and dorsal root ganglia in diabetic neuropathy in rats. Neurosci. Lett. 262, 159-162 (1999
111. Peng, L., Liu, W., Zhai, F., He, L., & Wang, H. Microvessel permeability correlates with diabetic peripheral neuropathy in early stage of streptozotocin-induced diabetes rats. J. Diabetes Complications 29, 865-871 (2015
112. Taiana, M. M., et al. Neutralization of Schwann cell-secreted VEGF is protective to in vitro and in vivo experimental diabetic neuropathy. PLoS ONE 9, e108403 (2014
113. Schratzberger, P., et al. Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy. Nat. Med. 6, 405-413 (2000
114. Verheyen, A., et al. Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy. Brain 135, 2629-2641 (2012
115. Verheyen, A., et al. Therapeutic potential of VEGF and VEGF-derived peptide in peripheral neuropathies. Neuroscience 244, 77-89 (2013
116. Bates, D. O., et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res. 62, 4123-4131 (2002
117. Woolard, J., 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. 64, 7822-7835 (2004
118. Beazley-Long, N., et al. VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro. Am J. Pathol. 183, 918-929 (2013
119. Hulse, R. P., et al. Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration. Clin. Sci. (Lond.) 129, 741-756 (2015
120. Dhondt, J., et al. Neuronal FLT1 receptor and its selective ligand VEGF B protect against retrograde degeneration of sensory neurons. FASEB J. 25, 1461-1473 (2011
121. Selvaraj, D., et al. A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell 27, 780-796 (2015
122. Simovic, D., Isner, J. M., Ropper, A. H., Pieczek, A., & Weinberg, D. H. Improvement in chronic ischemic neuropathy after intramuscular phVEGF165 gene transfer in patients with critical limb ischemia. Arch. Neurol. 58, 761-768 (2001
123. Ropper, A. H., et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial. Ann. Neurol. 65, 386-393 (2009
124. Ma, Y., Zechariah, A., Qu, Y., & Hermann, D. M. Effects of vascular endothelial growth factor in ischemic stroke. J. Neurosci. Res. 90, 1873-1882 (2012
125. Zhang, Z. G., et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Invest. 106, 829-838 (2000
126. van Bruggen, N., et al. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J. Clin. Invest. 104, 1613-1620 (1999
127. Lu, K. T., et al. Hippocampal neurogenesis after traumatic brain injury is mediated by vascular endothelial growth factor receptor 2 and the Raf/MEK/ERK cascade. J. Neurotrauma 28, 441-450 (2011
128. Marti, H. J., et al. Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am. J. Pathol. 156, 965-976 (2000
129. Baumann, G., Travieso, L., Liebl, D. J., & Theus, M. H. Pronounced hypoxia in the subventricular zone following traumatic brain injury and the neural stem/progenitor cell response. Exp. Biol. Med. 238, 830-841 (2013
130. Thored, P., et al. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke 38, 3032-3039 (2007
131. Mellergerd, P., Sjfgren, F., & Hillman, J. Release of VEGF and FGF in the extracellular space following severe subarachnoidal haemorrhage or traumatic head injury in humans. Br. J. Neurosurg. 24, 261-267 (2010
132. Slevin, M., et al. Serial measurement of vascular endothelial growth factor and transforming growth factor β1 in serum of patients with acute ischemic stroke. Stroke 31, 1863-1870 (2000
133. Pikula, A., et al. Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study. Stroke 44, 2768-2775 (2013
134. Lapilover, E. G., et al. Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol. Dis. 48, 495-506 (2012
135. Terpolilli, N. A., et al. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ. Res. 110, 727-738 (2012
136. Moisan, A., et al. Microvascular plasticity after experimental stroke: a molecular and MRI study. Cerebrovasc. Dis. 38, 344-353 (2014
137. Greenberg, D. A., & Jin, K. Vascular endothelial growth factors (VEGFs) and stroke. Cell. Mol. Life Sci. 70, 1753-1761 (2013
138. Svensson, B., et al. Vascular endothelial growth factor protects cultured rat hippocampal neurons against hypoxic injury via an antiexcitotoxic, caspase-independent mechanism. J. Cereb. Blood Flow Metab. 22, 1170-1175 (2002
139. Thau-Zuchman, O., Shohami, E., Alexandrovich, A. G., & Leker, R. R. Vascular endothelial growth factor increases neurogenesis after traumatic brain injury. J. Cereb. Blood Flow Metab. 30, 1008-1016 (2010
140. Tado, M., et al. Increased expression of vascular endothelial growth factor attenuates contusion necrosis without influencing contusion edema after traumatic brain injury in rats. J. Neurotrauma 31, 691-698 (2014
141. Gaal, E. I., et al. Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization. Blood 122, 658-665 (2013
142. Siddiq, I., et al. Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF A. J. Neurotrauma 29, 2647-2659 (2012
143. D'Andrea, L. D., et al. Targeting angiogenesis: structural characterization and biological properties of a De novo engineered VEGF mimicking peptide. Proc. Natl Acad. Sci. USA 102, 14215-14220 (2005
144. Pignataro, G., et al. Neuroprotective effect of VEGF-mimetic peptide QK in experimental brain ischemia induced in rat by middle cerebral artery occlusion. ACS Chem. Neurosci. 6, 1517-1525 (2015
145. Maxwell, P. H., & Eckardt, K. U. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat. Rev. Nephrol. 12, 157-168 (2016
146. Kunze, R., et al. Neuron-specific prolyl-4 hydroxylase domain 2 knockout reduces brain injury after transient cerebral ischemia. Stroke 43, 2748-2756 (2012
147. Reischl, S., et al. Inhibition of HIF prolyl-4 hydroxylases by FG 4497 reduces brain tissue injury and edema formation during ischemic stroke. PLoS ONE 9, e84767 (2014
148. Ogle, M. E., Gu, X., Espinera, A. R., & Wei, L. Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor 1α. Neurobiol. Dis. 45, 733-742 (2012
149. Bernaudin, M., et al. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor 1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J. Cereb. Blood Flow Metab. 22, 393-403 (2002
150. Quaegebeur, A., et al. Deletion or inhibition of the oxygen sensor PHD1 protects against ischemic stroke via reprogramming of neuronal metabolism. Cell Metab. 23, 280-291 (2016
151. Segura, I., et al. The oxygen sensor PHD2 controls dendritic spines and synapses via modification of filamin A. Cell Rep. 14, 2653-2667 (2016
152. Zhang, J., & Chopp, M. Cell-based therapy for ischemic stroke. Expert Opin. Biol. Ther. 13, 1229-1240 (2013
153. Wang, J., et al. Preconditioning with VEGF enhances angiogenic and neuroprotective effects of bone marrow mononuclear cell transplantation in a rat model of chronic cerebral hypoperfusion. Mol. Neurobiol. http://dx.doi.org/10.1007/s12035-015-9512-8 (2015
154. Rigau, V., et al. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 130, 1942-1956 (2007
155. Croll, S. D., Goodman, J. H., & Scharfman, H. E. Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword. Adv. Exp. Med. Biol. 548, 57-68 (2004
156. van Vliet, E. A., et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521-534 (2007
157. Tomkins, O., et al. Blood-brain barrier disruption results in delayed functional and structural alterations in the rat neocortex. Neurobiol. Dis. 25, 367-377 (2007
158. Obermeier, B., Daneman, R., & Ransohoff, R. M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584-1596 (2013
159. Morin-Brureau, M., et al. Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: role of VEGF signaling pathways. J. Neurosci. 31, 10677-10688 (2011
160. Nicoletti, J. N., et al. Vascular endothelial growth factor attenuates status epilepticus-induced behavioral impairments in rats. Epilepsy Behav. 19, 272-277 (2010
161. Nicoletti, J. N., et al. Vascular endothelial growth factor is up regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. Neuroscience 151, 232-241 (2008
162. Nikitidou, L., et al. VEGF receptor 2 (Flk 1) overexpression in mice counteracts focal epileptic seizures. PLoS ONE 7, e40535 (2012
163. Tomizawa, Y., et al. Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability. J. Int. Med. Res. 40, 1483-1491 (2012
164. Minagar, A., & Alexander, J. S. Blood-brain barrier disruption in multiple sclerosis. Mult. Scler. 9, 540-549 (2003
165. Su, J. J., et al. Upregulation of vascular growth factors in multiple sclerosis: correlation with MRI findings. J. Neurol. Sci. 243, 21-30 (2006
166. Shimizu, F., et al. Sera from neuromyelitis optica patients disrupt the blood-brain barrier. J. Neurol. Neurosurg. Psychiatry 83, 288-297 (2012
167. Proescholdt, M. A., Jacobson, S., Tresser, N., Oldfield, E. H., & Merrill, M. J. Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J. Neuropathol. Exp. Neurol. 61, 914-925 (2002
168. Argaw, A. T., et al. IL 1β regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J. Immunol. 177, 5574-5584 (2006
169. Argaw, A. T., et al. Astrocyte-derived VEGF A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest. 122, 2454-2468 (2012
170. MacMillan, C. J., et al. Bevacizumab diminishes experimental autoimmune encephalomyelitis by inhibiting spinal cord angiogenesis and reducing peripheral T cell responses. J. Neuropathol. Exp. Neurol. 71, 983-999 (2012
171. Mantel, I. Optimizing the anti-VEGF treatment strategy for neovascular age-related macular degeneration: from clinical trials to real-life requirements. Transl. Vis. Sci. Technol. 4, 6 (2015
172. Baker, C. W., Jiang, Y., & Stone, T. Recent advancements in diabetic retinopathy from the Diabetic Neuropathy Clinical Research Network. Curr. Opin. Ophthalmol. 27, 210-216 (2016
173. Jin, K., Wang, X., Xie, L., Mao, X. O., & Greenberg, D. A. Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice. Proc. Natl Acad. Sci. USA 107, 7993-7998 (2010
174. Blaiss, C. A., et al. Temporally specified genetic ablation of neurogenesis impairs cognitive recovery after traumatic brain injury. J. Neurosci. 31, 4906-4916 (2011
175. Kirby, E. D., Kuwahara, A. A., Messer, R. L., & Wyss-Coray, T. Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF. Proc. Natl Acad. Sci. USA 112, 4128-4133 (2015
176. Cao, L., et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat. Genet. 36, 827-835 (2004
177. Jin, K., et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad. Sci. USA 99, 11946-11950 (2002
178. Fabel, K., et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur. J. Neurosci. 18, 2803-2812 (2003
179. Sun, Y., et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J. Clin. Invest. 111, 1843-1851 (2003
180. Lee, C., & Agoston, D. V. Inhibition of VEGF receptor 2 increased cell death of dentate hilar neurons after traumatic brain injury. Exp. Neurol. 220, 400-403 (2009
181. Licht, T., et al. Reversible modulations of neuronal plasticity by VEGF. Proc. Natl Acad. Sci. USA 108, 5081-5086 (2011
182. Cattin, A. L., et al. Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves. Cell 162, 1127-1139 (2015
183. Cho, Y., et al. Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF 1α. Neuron 88, 720-734 (2015
184. Ambati, J., & Fowler, B. J. Mechanisms of age-related macular degeneration. Neuron 75, 26-39 (2012
185. Miller, J. W., Adamis, A. P., & Aiello, L. P. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. Diabetes Metab. Rev. 13, 37-50 (1997
186. Lai, C. M., et al. Generation of transgenic mice with mild and severe retinal neovascularisation. Br. J. Ophthalmol. 89, 911-916 (2005
187. Shen, W. Y., et al. Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model. Diabetologia 49, 1690-1701 (2006
188. van Eeden, P. E., et al. Early vascular and neuronal changes in a VEGF transgenic mouse model of retinal neovascularization. Invest. Ophthalmol. Vis. Sci. 47, 4638-4645 (2006
189. Wang, F., et al. AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat. Invest. Ophthalmol. Vis. Sci. 44, 781-790 (2003
190. Huang, H., et al. Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition. Diabetes 64, 200-212 (2015
191. Lazzeri, S., et al. Aflibercept administration in neovascular age-related macular degeneration refractory to previous anti-vascular endothelial growth factor drugs: a critical review and new possible approaches to move forward. Angiogenesis 18, 397-432 (2015
192. Van De Veire, S., et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141, 178-190 (2010
193. Rakic, J. M., et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 44, 3186-3193 (2003
194. Nishijima, K., et al. Vascular endothelial growth factor A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am. J. Pathol. 171, 53-67 (2007
195. Foxton, R. H., et al. VEGF A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. Am. J. Pathol. 182, 1379-1390 (2013
196. Park, H. Y., Kim, J. H., & Park, C. K. Neuronal cell death in the inner retina and the influence of vascular endothelial growth factor inhibition in a diabetic rat model. Am. J. Pathol. 184, 1752-1762 (2014