- •Preface
- •Contents
- •Contributors
- •1: Living with Diabetic Retinopathy: The Patient’s View
- •My Patient Experience
- •Others’ Experiences
- •Photos of the Meaning of Diabetes
- •References
- •2: Diabetic Retinopathy Screening: Progress or Lack of Progress
- •Definitions of Screening for Diabetic Retinopathy
- •Studies Reporting the Prevalence of Diabetic Retinopathy
- •Reports on Blindness and Visual Impairment
- •Is There Evidence That Treatment for Sight-Threatening Diabetic Retinopathy Is Effective and Agreed Universally?
- •The Evidence That Diabetic Retinopathy Can Be Prevented or the Rate of Deterioration Reduced by Improved Control of Blood Glucose, Blood Pressure and Lipid Levels, and by Giving Up Smoking
- •The Evidence that Laser Treatment Is Effective
- •The Evidence That Vitrectomy for More Advanced Disease Is Effective
- •Progress of Lack of Progress in Screening for Diabetic Retinopathy in Different Parts of the World
- •References
- •3: Functional/Neural Mapping Discoveries in the Diabetic Retina: Advancing Clinical Care with the Multifocal ERG
- •Introduction
- •The Diabetes Epidemic
- •Current Treatment Focus
- •Vasculopathy and Neuropathy of the Retina
- •The Early Efforts
- •Some Breakthroughs
- •Predictive Models of Visible Retinopathy Onset at Specific Locations
- •How Is the mfERG Measured and What is it Measuring?
- •Where Are These Neural Signals Generated in the Retina?
- •Some Key Results
- •Adolescents and Adult Diabetes
- •Type 1 vs. Type 2: Differences in Retinal Function
- •References
- •4: Corneal Diabetic Neuropathy
- •Introduction
- •Corneal Confocal Microscopy
- •Corneal Nerves and Diabetes
- •Conclusion
- •References
- •5: Clinical Phenotypes of Diabetic Retinopathy
- •Natural History
- •MA Formation and Disappearance Rates
- •Alteration of the Blood–Retinal Barrier
- •Retinal Capillary Closure
- •Multimodal Macula Mapping
- •Clinical Retinopathy Phenotypes
- •Relevance for Clinical Trial Design
- •Relevance for Clinical Management
- •Targeted Treatments
- •References
- •6: Visual Psychophysics in Diabetic Retinopathy
- •Introduction
- •Visual Acuity
- •Color Vision
- •Contrast Sensitivity
- •Macular Recovery Function (Nyctometry)
- •Perimetry
- •Microperimetry (Fundus-Related Perimetry)
- •Conclusion
- •References
- •7: Mechanisms of Blood–Retinal Barrier Breakdown in Diabetic Retinopathy
- •The Protective Barriers of the Retina
- •The Inner and the Outer BRB
- •Inflammation and BRB Permeability
- •Leukocyte Mediators of Vascular Leakage
- •Other Mediators of Leukocyte Recruitment in DR
- •Structural Compromise of the BRB
- •Vascular Endothelial Growth Factor
- •Anti-VEGF Properties of Natriuretic Peptides
- •Proposed Model of BRB Breakdown in DR
- •Key Role of AZ in VEGF-Induced Leakage
- •Azurocidin Inhibition Prevents Diabetic Retinal Vascular Leakage
- •References
- •8: Molecular Regulation of Endothelial Cell Tight Junctions and the Blood-Retinal Barrier
- •The Blood-Retinal Barrier
- •The Retinal Vascular Barrier
- •The Junctional Complex
- •ZO Proteins
- •Claudins
- •Junctional Adhesion Molecules
- •Occludin and Tricellulin
- •Vascular Permeability in Diabetic Retinopathy
- •VEGF-Induced Regulation of Endothelial Permeability
- •Occludin Phosphorylation and Permeability
- •Protein Kinase C in Regulation of Barrier Properties
- •Conclusions
- •References
- •9: Capillary Degeneration in Diabetic Retinopathy
- •Vascular Nonperfusion in Diabetes: Mechanisms
- •Molecular Causes of Capillary Degeneration
- •Unexplained Aspects of Diabetes-Induced Degeneration of Retinal Capillaries
- •What Is the Relation Between the Retinal Vasculature and Neuronal Retina Structure and Function in Diabetes?
- •Conclusion
- •References
- •10: Proteases in Diabetic Retinopathy
- •Proteases in Retinal Vasculature
- •Extracellular Proteases
- •Urokinase Plasminogen Activator System (uPA/uPAR System)
- •Matrix Metalloproteinases
- •Endogenous Inhibitors of Proteases
- •Tissue Inhibitors of Metalloproteinases (TIMPs)
- •Plasminogen Activator Inhibitors (PAI)
- •Proteases in Retinal Neovascularization
- •Tissue Inhibitor of Matrix Metalloproteinases in Retinal Neovascularization
- •Inhibition of Retinal Angiogenesis by MMP Inhibitors
- •Inhibition of Retinal Angiogenesis by Inhibitors of the uPA/uPAR System
- •Proteases in Diabetic Macular Edema
- •Conclusion
- •References
- •11: Proteomics in the Vitreous of Diabetic Retinopathy Patients
- •Introduction
- •Vitreous Anatomy
- •A Candidate Approach
- •Proteomic Approaches
- •Vitreous Acquisition
- •Sample Pre-Fractionation
- •Mass Spectrometry
- •Spectral Analysis
- •Data Analysis
- •The Vitreous Proteome
- •2-DE-Based Proteomics
- •1-DE-Based Proteomics
- •Summary and Conclusions
- •References
- •12: Neurodegeneration in Diabetic Retinopathy
- •Introduction
- •Histological Evidence
- •Early Pathology Studies
- •Histological Evidence of Apoptosis
- •Gross Morphological Changes in the Retina
- •Reductions in Numbers of Surviving Amacrine Cells
- •Retinal Ganglion Cell Loss
- •Abnormalities in Ganglion Cell Morphology
- •Centrifugal Axon Abnormalities
- •Nerve Fiber Layer Thickness
- •Biochemical Evidence of Neurodegeneration and Cell Death
- •Functional Evidence of Neurodegenerative Changes
- •Electrophysiological Evidence for Neurodegeneration
- •Optic Nerve Retrograde Transport
- •Other Changes in Visual Function
- •Summary and Conclusions
- •References
- •13: Glucose-Induced Cellular Signaling in Diabetic Retinopathy
- •Introduction
- •Cellular Targets in DR
- •Endothelial Cell (EC) Dysfunction
- •Endothelial-Pericyte Interactions
- •Endothelial-Matrix Interactions
- •Signaling Mechanisms in DR
- •Altered Vasoactive Factors
- •Alteration of Metabolic Pathways
- •Polyol Pathway
- •Hexosamine Pathway
- •Protein Kinase C Pathway
- •Activation of Other Protein Kinases
- •Mitogen-Activated Protein Kinase (MAPK)
- •Increased Oxidative Stress
- •Protein Glycation
- •Aberrant Expression of Growth Factors
- •Transcription Factors
- •Transcription Regulators
- •Concluding Remarks
- •References
- •Introduction
- •The Growth-Hormone/Insulin-Like Growth Factor Pathway in Proliferative Retinopathies
- •Proliferative Diabetic Retinopathy (PDR)
- •Retinopathy of Prematurity (ROP)
- •Animal Models of Proliferative Retinopathies
- •IGFBP-3 as a Regulator of the Growth-Hormone/ Insulin-Like Growth Factor Pathway
- •Conclusion
- •References
- •15: Neurotrophic Factors in Diabetic Retinopathy
- •Diabetic Retinopathy
- •Neurotrophic Factors
- •Neurotrophins and Others
- •Nerve Growth Factor
- •Glial-Cell-Derived Neurotrophic Factor
- •Ciliary Neurotrophic Factor
- •Anti-angiogenic Neurotrophic Factors
- •Pigment-Epithelium-Derived Factor
- •SERPINA3K
- •Brain-Derived Neurotrophic Factor
- •Fibroblast Growth Factors
- •Insulin and Insulin-Like Growth Factor 1
- •Erythropoietin
- •Vascular Endothelial Growth Factor
- •Neurotrophic Factors and the Future of DR Research
- •References
- •16: The Role of CTGF in Diabetic Retinopathy
- •Introduction
- •ECM Remodeling and Wound Healing Mechanisms in Diabetic Retinopathy
- •ECM Remodeling in PCDR
- •Wound Healing Mechanisms in PDR
- •CTGF Structure and Function
- •CTGF in the Eye
- •CTGF in Ocular Fibrosis
- •CTGF in Ocular Angiogenesis
- •CTGF in Diabetic Retinopathy
- •CTGF in BL Thickening in PCDR
- •AGEs and CTGF in BL Thickening in PCDR
- •Role of VEGF in BL Thickening
- •BL Thickening in Diabetic CTGF-Knockout Mice
- •CTGF in PDR
- •Role of CTGF and VEGF in the “Angiofibrotic Switch” in PDR
- •Conclusions
- •References
- •17: Ranibizumab and Other VEGF Antagonists for Diabetic Macular Edema
- •Introduction
- •Pathogenesis of DME and Current Standard of Care
- •Ranibizumab for DME
- •Pegaptanib for DME
- •Bevacizumab for DME
- •VEGF Trap-Eye for DME
- •Other Considerations in the Management of DME
- •Combination Treatment for DME
- •DME and Quality of Life
- •Conclusions
- •References
- •18: Neurodegeneration, Neuropeptides, and Diabetic Retinopathy
- •Introduction
- •Neuropeptides Involved in the Pathogenesis of DR
- •Glutamate
- •Angiotensin II
- •Pigment Epithelial-Derived Factor
- •Somatostatin
- •Erythropoietin
- •Docosahexaenoic Acid and Neuroprotectin D1
- •Brain-Derived Neurotrophic Factor
- •Glial Cell Line-Derived Neurotrophic Factor
- •Ciliary Neurotrophic Factor
- •Adrenomedullin
- •Concluding Remarks and Therapeutic Implications
- •References
- •19: Glial Cell–Derived Cytokines and Vascular Integrity in Diabetic Retinopathy
- •Introduction
- •The BRB Functional Unit Composed of Glial and Endothelial Cells
- •Tight Junctions Between Endothelial Cells Are Substantial Barrier of the BRB
- •Major Cytokines Derived from Glial Cells Affecting Tight Junctions of the BRB
- •VEGF
- •GDNF
- •APKAP12
- •A Possible Treatment of the Retinopathy with Retinoic Acid Analogues
- •Conclusion
- •References
- •20: Impact of Islet Cell Transplantation on Diabetic Retinopathy in Type 1 Diabetes
- •Introduction
- •What Are the Benefits and Risks of Reducing Blood Glucose?
- •On Average, 3 Years Was Required to Demonstrate the Beneficial Effect of Intensive Treatment
- •The Earlier in the Course of Diabetes That Intensive Therapy Is Initiated, Even Before the Onset of Retinopathy, the Greater the Long-Term Benefits
- •Risk Reduction in the Primary Prevention Cohort
- •Risk Reduction in the Secondary Prevention Cohort
- •There Was No Glycemic Threshold Regarding Progression of Retinopathy
- •Diabetic Ketoacidosis (DKA)
- •Efforts to Normalize Blood Glucose Are Associated with Weight Gain in People with Type 1 Diabetes
- •Connecting Peptide (C-Peptide) Responders Have Less Risk of Progression of Retinopathy
- •Effects of Improved Control on Retinopathy Were Sustained in the Long-Term
- •Quality of Life Measure
- •“Metabolic Memory”: A Phenomenon Producing a Long-Term Beneficial Influence of Early Metabolic Control on Clinical Outcomes
- •Need for a More Physiologic Glycemic Control Regimen
- •Effect of Intensive Insulin Therapy on Hypoglycemia Counterregulation
- •b Cell Function
- •Whole Pancreas Transplantation
- •Effect of SPK Transplantation on Diabetic Retinopathy
- •Islet Cell Transplantation
- •Adverse Effects of Chronic Immunosuppression
- •Effect of Islet Cell Transplantation on Retinopathy
- •References
- •Index
Glial Cell–Derived Cytokines and Vascular Integrity |
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early phase of the disease. (3) RAs are promising candidates to prevent the progression of diabetic eye diseases, including retinopathy. It is worthy of mention that RAs downregulate VEGF expression in glial cells.
Lastly, we hope that many researchers focus their attention on the regulation of tight junctions of the BRB from the viewpoints mentioned above. In particular, since tight junctions of the BRB-forming endothelial cells are regulated by cytokines in a paracrine manner, mechanisms of cytokine secretion from glial cells should be elucidated to develop a new rational therapy of diabetic retinopathy.
REFERENCES
1.Kim JH, Kim JH, Park JA, et al. Blood-neural barrier: intercellular communication at gliovascular interface. J Biochem Mol Biol. 2006;39:339–45.
2. Cunha-Vaz JG. The blood-retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res. 2004;78:715–21.
3. Sawada N, Murata M, Kikuchi K, et al. Tight junctions and human diseases. Med Electron Microsc. 2003;36:147–56.
4. Miyajima H, Osanai M, Chiba H, et al. Glyceroaldehyde-derived advanced glycation endproducts preferentially induce VEGF expression and reduce GDNF expression in human astrocytes. Biochem Biophys Res Commun. 2005;330:361–6.
5. IgarashiY,UtsumiH,ChibaH,etal.Glialcellline-derivedneurotrophicfactorinducesbarrierfunc- tionofendothelialcellsformingtheblood-brainbarrier.BiochemBiophysResCommun.1999;261: 108–12.
6.IgarashiY,ChibaH,SawadaN,etal.Expressionofreceptorsforglialcellline-derivedneurotrophic factor(GDNF)andneurturinintheinnerblood–retinalbarrierofrats.CellStructFunct.2000;25: 237–41.
7. Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30:949–57.
8. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res. 2008;27:622–47.
9.Luna JD, Chan CC, Derevjanik NL, et al. Blood-retinal barrier (BRB) breakdown in experimental autoimmune uveoretinitis: comparison with vascular endothelial growth factor, tumor necrosis factor a, and interleukin-1b-mediated breakdown. J Neurosci Res. 1997;49:268–80.
10. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res. 2008;27:622–47.
11. Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350:48–58.
12. Miyamoto K, Khosrof S, Bursell SE, et al. Vascular endothelial growth factor (VEGF)- induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol. 2000;156:1733–9.
13. Joussen AM, Poulaki V, Qin W, et al. Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol. 2002;160:501–9.
14. Qaum T, Xu Q, Joussen AM, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001;42:2408–13.
15. Ishida S, Usui T, Yamashiro K, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci. 2003;44:2155–62.
16. Barile GR, Chang SS, Park LS, Reppucci VS, Schiff WM, Schmidt AM. Soluble cellular adhesion molecules in proliferative vitreoretinopathy and proliferative diabetic retinopathy. Curr Eye Res. 1999;19:219–27.
336 |
Inatomi et al. |
17. Hernández C, Burgos R, Cantón A, Garcia-Arumi J, Segura RM, Simó R. Vitreous levels of vascular cell adhesion molecule and vascular endothelial growth factor in patients with proliferative diabetic retinopathy: a case-control study. Diabetes Care. 2001;24:516–21.
18.DemircanN,SafranBG,SoyluM,OzcanAA,SizmazS.Determinationofvitreousinterleukin-1 (IL-1)andtumornecrosisfactor(TNF)levelsinproliferativediabeticretinopathy.Eye.2006;20: 1366–9.
19. Doganay S, Evereklioglu C, Er H, et al. Comparison of serum NO, TNF-a, IL-1b, sIL2R, IL-6 and IL-8 levels with grades of retinopathy in patients with diabetes mellitus. Eye. 2002;16:163–70.
20. Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: Implications for structural differences in macular profiles. Exp Eye Res. 2006;82:798–806.
21. Nishikiori N, Osanai M, Chiba H, et al. Glial cell-derived cytokines attenuates the breakdown of vascular integrity in diabetic retinopathy. Diabetes. 2007;56:1333–40.
22. Nishikiori N, Osanai M, Chiba H, et al. Glial cell line-derived neurotrophic factor in the vitreous of patients with proliferative diabetic retinopathy. Diabetes Care. 2005;28:2588.
23. Yuuki T, Kanda T, Kimura Y, et al. Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. J Diabetes Complications. 2001;15:257–9.
24. Nebme A, Edelman J. Dexamethasone inhibits high glucose-, TNF-a, and IL-1b-induced secretion of inflammatory and angiogenic mediators from retinal microvascular pericytes. Invest Ophthalmol Vis Sci. 2008;49:2030–8.
25. Abott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.
26. Balda MS, Matter K. Tight junctions at a glance. J Cell Sci. 2008;15:3677–82.
27. Tsukita S, Furuse M, Itoh M. Structural and signalling molecules come together at tight junctions. Curr Opin Cell Biol. 1999;11:628–33.
28. Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2001;2:285–93.
29. Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol. 2003;4:225–36.
30. Chiba H, Osanai M, Murata M, Kojima T, Sawada N. Transmembrane proteins of tight junctions. Biochim Biophys Acta. 2008;1778:588–600.
31. Schneeberger EE, Lynch RD. The tight junction: a multifunctional complex. Am J Physiol Cell Physiol. 2004;286:1213–28.
32. Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol. 2005;171:939–45.
33. Umeda K, Ikenouchi J, Katahira-Tayama S, et al. ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell. 2006;25(126): 741–54.
34. Nitta T, Hata M, Gotoh S, et al. Size-selective loosening of the blood-brain barrier in claudin- 5-deficient mice. J Cell Biol. 2003;161:653–60.
35. Fontijn RD, Volger OL, Fledderus JO, Reijerkerk A, de Vries HE, Horrevoets AJ. SOX-18 controls endothelial-specific claudin-5 gene expression and barrier function. Am J Physiol Heart Circ Physiol. 2008;294:891–900.
36. Taddei A, Giampietro C, Conti A, et al. Endothelial adherens junctions control tight junction by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol. 2008;10:923–34.
37. Ishizaki T, Chiba H, Kojima T, et al. Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways. Exp Cell Res. 2003;290:275–88.
Glial Cell–Derived Cytokines and Vascular Integrity |
337 |
38. Soma T, Chiba H, Kato-Mori Y, et al. Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP. Exp Cell Res. 2004;300:202–12.
39. Yamamoto M, Ramirez SH, Sato S, et al. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol. 2008;172:521–33.
40. Liebner S, Corada M, Bangsow T, Gerhardt H, Dejana E, et al. Wnt/b-catenin signaling controls development of the blood-brain barrier. J Cell Biol. 2008;183:409–17.
41. Sun M, Fink PJ. A new class of reverse signaling costimulators belongs to the TNF family. J Immunol. 2007;179:4307–12.
42. Vinay DS, Kwon BS. TNF superfamily: costimulation and clinical applications. Cell Biol Int. 2009;33:453–65.
43. Limb GA, Chignell AH, Green W, LeRoy F, Dumonde DC. Distribution of TNF a and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy. Br J Ophthalmol. 1996;80:168–73.
44. Limb GA, Soomro H, Janikoun S, Hollifield RD, Shilling J. Evidence for control of tumour necrosis factor-alpha (TNF-a) activity by TNF receptors in patients with proliferative diabetic retinopathy. Clin Exp Immunol. 1999;115:409–14.
45. Hawrami K, Hitman GA, Rema M, et al. An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. Hum Immunol. 1996;46:49–54.
46. Mullin JM, Snock KV. Effect of tumor necrosis factor on epithelial tight junctions and transepithelial permeability. Cancer Res. 1990;50:2172–6.
47. Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990;4:2860–7.
48. Li J, Perrella MA, Tsai JC, et al. Induction of vascular endothelial growth factor gene expression by interleukin-1b in rat aortic smooth muscle cells. J Biol Chem. 1995;270:308–12.
49. Camussi G, Albano E, Tetta C, Bussolino F. The molecular action of tumor necrosis factor- a. Eur J Biochem. 1991;202:3–14.
50. Harada S, Nagy JA, Sullivan KA, et al. Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J Clin Invest. 1994;93:2490–6.
51. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843–5.
52. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.
53.IkedaE,AchenMG,BreierG,RisauW.Hypoxia-inducedtranscriptionalactivationandincreased mRNAstabilityofvascularendothelialgrowthfactorinC6gliomacells.JBiolChem.1995;270: 19761–6.
54. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–5.
55. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995;146:1029–39.
56. Barouch FC, Miyamoto K, Allport JR, et al. Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest Ophthalmol Vis Sci. 2000;41:1153–8.
57. Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/ vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA. 1995;92:905–9.
58. Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K. The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas. Lab Invest. 1996;74:819–25.
338 |
Inatomi et al. |
59. Ng EW, Shima DT, Calias P, Cunningham Jr ET, Guyer DR, Adamis AP. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006;5:123–32.
60. Comer GM, Ciulla TA. Pharmacotherapy for diabetic retinopathy. Curr Opin Ophthalmol. 2004;15:508–18.
61. Rodewald M, Herr D, Fraser HM, Hack G, Kreienberg R, Wulff C. Regulation of tight junction proteins occludin and claudin 5 in the primate ovary during the ovulatory cycle and after inhibition of vascular endothelial growth factor. Mol Hum Reprod. 2007;13:781–9.
62. Antonetti DA, Barber AJ, Khin S, Lieth E, Tarbell JM, Gardner TW. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. Diabetes. 1998;47:1953–9.
63. Lin LF, Dohery DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260:1130–2.
64. Henderson CE, Phillips HS, Pollock RA, et al. GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science. 1994;266:1062–4.
65. Utsumi H, Chiba H, Kamimura Y, et al. Expression of GFRalpha-1, receptor for GDNF, in rat brain capillary during postnatal development of the BBB. Am J Physiol Cell Physiol. 2000;279:361–8.
66. Lee SW, Kim WJ, Choi YK, et al. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med. 2003;9:828–9.
67. Choi YK, Kim JH, Kim WJ, et al. AKAP12 regulates human blood-retinal barrier formation by downregulation of hypoxia-inducible factor-1a. J Neurosci. 2007;27:4472–81.
68. Bamforth SD, Lightman S, Greenwood J. The effect of TNF-a and IL-6 on the permeability of the rat blood-retinal barrier in vivo. Acta Neuropathol. 1996;91:624–32.
69. Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci. 2007;8:755–65.
70. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. J Neurobiol. 2006;66:606–30.
71. Bastien J, Rochette-Egly C. Nuclear retinoid receptors and the transcription of retinoidtarget genes. Gene. 2004;328:1–16.
72. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002;43:1773–808.
73. Thang SH, Kobayashi M, Matsuoka I. Regulation of glial cell line-derived neurotrophic factor responsiveness in developing rat sympathetic neurons by retinoic acid and bone morphogenetic protein-2. J Neurosci. 2000;20:2917–25.