Table of Contents Author Guidelines Submit a Manuscript
Journal of Ophthalmology
Volume 2012, Article ID 209538, 14 pages
http://dx.doi.org/10.1155/2012/209538
Review Article

Vascular Complications and Diabetes: Current Therapies and Future Challenges

1Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA
2Center for Innovations in Wound Healing Research, Tufts University School of Medicine, Tufts University, Boston, MA 02111, USA

Received 1 August 2011; Accepted 2 October 2011

Academic Editor: Toshiaki Kubota

Copyright © 2012 Abbott L. Willard and Ira M. Herman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. M. Joussen, V. Poulaki, W. Qin 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,” American Journal of Pathology, vol. 160, no. 2, pp. 501–509, 2002. View at Google Scholar · View at Scopus
  2. H. Shamoon, H. Duffy, N. Fleischer et al., “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 329, no. 14, pp. 977–986, 1993. View at Publisher · View at Google Scholar
  3. R. Turner, “Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33),” The Lancet, vol. 352, no. 9131, pp. 837–853, 1998. View at Publisher · View at Google Scholar
  4. S. Wild, G. Roglic, A. Green, R. Sicree, and H. King, “Global prevalence of diabetes: estimates for the year 2000 and projections for 2030,” Diabetes Care, vol. 27, no. 5, pp. 1047–1053, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. T. N. Crawford, D. V. Alfaro, J. B. Kerrison, and E. P. Jablon, “Diabetic retinopathy and angiogenesis,” Current Diabetes Reviews, vol. 5, no. 1, pp. 8–13, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. R. Klein, B. E. K. Klein, S. E. Moss, and K. J. Cruickshanks, “The Wisconsin epidemiologic study of diabetic retinopathy XV: the long-term incidence of macular edema,” Ophthalmology, vol. 102, no. 1, pp. 7–16, 1995. View at Google Scholar · View at Scopus
  7. “Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group,” Ophthalmology, vol. 88, no. 7, pp. 583–600, 1981.
  8. “Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group,” Ophthalmology, vol. 98, supplement 5, pp. 766–785, 1991.
  9. J. Chen, K. M. Connor, C. M. Aderman, K. L. Willett, O. P. Aspegren, and L. E. H. Smith, “Suppression of retinal neovascularization by erythropoietin siRNA in a mouse model of proliferative retinopathy,” Investigative Ophthalmology and Visual Science, vol. 50, no. 3, pp. 1329–1335, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. N. Cheung, P. Mitchell, and T. Y. Wong, “Diabetic retinopathy,” The Lancet, vol. 376, no. 9735, pp. 124–136, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. Q. Mohamed, M. C. Gillies, and T. Y. Wong, “Management of diabetic retinopathy: a systematic review,” Journal of the American Medical Association, vol. 298, no. 8, pp. 902–916, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. J. M. Adams and S. Cory, “The Bcl-2 protein family: arbiters of cell survival,” Science, vol. 281, no. 5381, pp. 1322–1326, 1998. View at Google Scholar · View at Scopus
  13. F. Podestà, G. Romeo, W. H. Liu et al., “Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro,” American Journal of Pathology, vol. 156, no. 3, pp. 1025–1032, 2000. View at Google Scholar · View at Scopus
  14. G. A. Limb, A. H. Chignell, W. Green, F. LeRoy, and D. C. Dumonde, “Distribution of TNFα and its reactive vascular adhesion molecules in fibrovascular membranes of proliferative diabetic retinopathy,” British Journal of Ophthalmology, vol. 80, no. 2, pp. 168–173, 1996. View at Google Scholar · View at Scopus
  15. Y. Behl, P. Krothapalli, T. Desta, A. DiPiazza, S. Roy, and D. T. Graves, “Diabetes-enhanced tumor necrosis factor-α production promotes apoptosis and the loss of retinal microvascular cells in type 1 and type 2 models of diabetic retinopathy,” American Journal of Pathology, vol. 172, no. 5, pp. 1411–1418, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. I. Tack, S. J. Elliot, M. Potier, A. Rivera, G. E. Striker, and L. J. Striker, “Autocrine activation of the IGF-I signaling pathway in mesangial cells isolated from diabetic NOD mice,” Diabetes, vol. 51, no. 1, pp. 182–188, 2002. View at Google Scholar · View at Scopus
  17. J.-E. Kim, R.-W. Park, J.-Y. Choi et al., “Molecular properties of wild-type and mutant βIG-H3 proteins,” Investigative Ophthalmology and Visual Science, vol. 43, no. 3, pp. 656–661, 2002. View at Google Scholar
  18. J. H. Han, S. W. Ha, I. K. Lee, B. W. Kim, and J. G. Kim, “High glucose-induced apoptosis in bovine retinal pericytes is associated with transforming growth factor β and βIG-H3: βIG-H3 induces apoptosis in retinal pericytes by releasing Arg-Gly-Asp peptides,” Clinical and Experimental Ophthalmology, vol. 38, no. 6, pp. 620–628, 2010. View at Publisher · View at Google Scholar
  19. P. Esser, K. Heimann, K. U. Bartz-Schmidt et al., “Apoptosis in proliferative vitreoretinal disorders: possible involvement of TGF-β-induced RPE cell apoptosis,” Experimental Eye Research, vol. 65, no. 3, pp. 365–378, 1997. View at Publisher · View at Google Scholar · View at Scopus
  20. J. E. Kim, S. J. Kim, B. H. Lee, R. W. Park, K. S. Kim, and I. S. Kim, “Identification of motifs for cell adhesion within the repeated domains of transforming growth factor-β-induced gene, βig-h3,” Journal of Biological Chemistry, vol. 275, no. 40, pp. 30907–30915, 2000. View at Google Scholar · View at Scopus
  21. R. G. LeBaron, K. I. Bezverkov, M. P. Zimber, R. Pavelec, J. Skonier, and A. F. Purchio, “βIG-H3, a novel secretory protein inducible by transforming growth factor-β, is present in normal skin and promotes the adhesion and spreading of dermal fibroblasts in vitro,” Journal of Investigative Dermatology, vol. 104, no. 5, pp. 844–849, 1995. View at Google Scholar · View at Scopus
  22. J. E. Kim, S. J. Kim, H. W. Jeong et al., “RGD peptides released from βig-h3, a TGF-β-induced cell-adhesive molecule, mediate apoptosis,” Oncogene, vol. 22, no. 13, pp. 2045–2053, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. C. D. Buckley, D. Pilling, N. V. Henriquez et al., “RGD peptides induce apoptosis by direct caspase-3 activation,” Nature, vol. 397, no. 6719, pp. 534–539, 1999. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Suri, P. F. Jones, S. Patan et al., “Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis,” Cell, vol. 87, no. 7, pp. 1171–1180, 1996. View at Publisher · View at Google Scholar · View at Scopus
  25. T. Hawighorst, M. Skobe, M. Streit et al., “Activation of the Tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs sauamous cell carcinoma growth,” American Journal of Pathology, vol. 160, no. 4, pp. 1381–1392, 2002. View at Google Scholar · View at Scopus
  26. D. Hanahan, “Signaling vascular morphogenesis and maintenance,” Science, vol. 277, no. 5322, pp. 48–50, 1997. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Cai, O. Kehoe, G. M. Smith, P. Hykin, and M. E. Boulton, “The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy,” Investigative Ophthalmology and Visual Science, vol. 49, no. 5, pp. 2163–2171, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. E. T. Cunningham Jr., A. P. Adamis, M. Altaweel et al., “A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema,” Ophthalmology, vol. 112, no. 10, pp. 1747–1757, 2005. View at Publisher · View at Google Scholar
  29. M. B. Sultan, D. Zhou, J. Loftus, T. Dombi, and K. S. Ice, “A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema,” Ophthalmology, vol. 118, no. 6, pp. 1107–1118, 2011. View at Publisher · View at Google Scholar
  30. P. Massin, F. Bandello, J. G. Garweg et al., “Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled, double-masked, multicenter phase II study,” Diabetes Care, vol. 33, no. 11, pp. 2399–2405, 2010. View at Publisher · View at Google Scholar
  31. P. Mitchell, F. Bandello, U. Schmidt-Erfurth et al., “The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema,” Ophthalmology, vol. 118, no. 4, pp. 615–625, 2011. View at Publisher · View at Google Scholar
  32. I. U. Scott, A. R. Edwards, R. W. Beck et al., “A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema,” Ophthalmology, vol. 114, no. 10, pp. 1860–1867, 2007. View at Google Scholar
  33. D. S. C. Lam, T. Y. Y. Lai, V. Y. W. Lee et al., “Efficacy of 1.25 mg versus 2.5 mg intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial,” Retina, vol. 29, no. 3, pp. 292–299, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Soheilian, A. Ramezani, A. Obudi et al., “Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema,” Ophthalmology, vol. 116, no. 6, pp. 1142–1150, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. R. Simó, E. Carrasco, M. García-Ramírez, and C. Hernández, “Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy,” Current Diabetes Reviews, vol. 2, no. 1, pp. 71–98, 2006. View at Publisher · View at Google Scholar · View at Scopus
  36. D. E. Sims, “Diversity within pericytes,” Clinical and Experimental Pharmacology and Physiology, vol. 27, no. 10, pp. 842–846, 2000. View at Publisher · View at Google Scholar · View at Scopus
  37. G. Allt and J. G. Lawrenson, “Pericytes: cell biology and pathology,” Cells Tissues Organs, vol. 169, no. 1, pp. 1–11, 2001. View at Publisher · View at Google Scholar · View at Scopus
  38. G. Bergers and S. Song, “The role of pericytes in blood-vessel formation and maintenance,” Neuro-Oncology, vol. 7, no. 4, pp. 452–464, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Motiejunaite and A. Kazlauskas, “Pericytes and ocular diseases,” Experimental Eye Research, vol. 86, no. 2, pp. 171–177, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. M. E. Kutcher and I. M. Herman, “The pericyte: cellular regulator of microvascular blood flow,” Microvascular Research, vol. 77, no. 3, pp. 235–246, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. L. Beck Jr. and P. A. D'Amore, “Vascular development: cellular and molecular regulation,” The FASEB Journal, vol. 11, no. 5, pp. 365–373, 1997. View at Google Scholar · View at Scopus
  42. D. C. Darland and P. A. D'Amore, “Cell cell interactions in vascular development,” Current Topics in Developmental Biology, vol. 52, pp. 107–149, 2001. View at Google Scholar · View at Scopus
  43. K. K. Hirschi and P. A. D'Amore, “Pericytes in the microvasculature,” Cardiovascular Research, vol. 32, no. 4, pp. 687–698, 1996. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Orlidge and P. A. D'Amore, “Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells,” Journal of Cell Biology, vol. 105, no. 3, pp. 1455–1462, 1987. View at Google Scholar · View at Scopus
  45. Y. Sato and D. B. Rifkin, “Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-β1-like molecule by plasmin during co-culture,” Journal of Cell Biology, vol. 109, no. 1, pp. 309–315, 1989. View at Google Scholar · View at Scopus
  46. M. Hellström, H. Gerhardt, M. Kalén et al., “Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis,” Journal of Cell Biology, vol. 152, no. 3, pp. 543–553, 2001. View at Google Scholar · View at Scopus
  47. P. Lindahl, B. R. Johansson, P. Levéen, and C. Betsholtz, “Pericyte loss and microaneurysm formation in PDGF-B-deficient mice,” Science, vol. 277, no. 5323, pp. 242–245, 1997. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Mizutani, T. S. Kern, and M. Lorenzi, “Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy,” Journal of Clinical Investigation, vol. 97, no. 12, pp. 2883–2890, 1996. View at Google Scholar · View at Scopus
  49. R. A. Kowluru and S. Odenbach, “Effect of long-term administration of α-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats,” Diabetes, vol. 53, no. 12, pp. 3233–3238, 2004. View at Publisher · View at Google Scholar · View at Scopus
  50. H. P. Hammes, J. Lin, P. Wagner et al., “Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy,” Diabetes, vol. 53, no. 4, pp. 1104–1110, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. F. Pfister, Y. Feng, F. V. Hagen et al., “Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy,” Diabetes, vol. 57, no. 9, pp. 2495–2502, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. P. Dore-Duffy, C. Owen, R. Balabanov, S. Murphy, T. Beaumont, and J. A. Rafols, “Pericyte migration from the vascular wall in response to traumatic brain injury,” Microvascular Research, vol. 60, no. 1, pp. 55–69, 2000. View at Publisher · View at Google Scholar · View at Scopus
  53. E. Gonul, B. Duz, S. Kahraman, H. Kayali, A. Kubar, and E. Timurkaynak, “Early pericyte response to brain hypoxia in cats: an ultrastructural study,” Microvascular Research, vol. 64, no. 1, pp. 116–119, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. M. C. Puri and A. Bernstein, “Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 22, pp. 12753–12758, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. M. E. Kutcher, A. Y. Kolyada, H. K. Surks, and I. M. Herman, “Pericyte Rho GTPase mediates both pericyte contractile phenotype and capillary endothelial growth state,” American Journal of Pathology, vol. 171, no. 2, pp. 693–701, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Kotecki, A. S. Zeiger, K. J. Van Vliet, and I. M. Herman, “Calpain- and talin-dependent control of microvascular pericyte contractility and cellular stiffness,” Microvascular Research, vol. 80, no. 3, pp. 339–348, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Porta, “Endothelium: the main actor in the remodelling of the retinal microvasculature in diabetes,” Diabetologia, vol. 39, no. 6, pp. 739–744, 1996. View at Publisher · View at Google Scholar · View at Scopus
  58. H. N. Antoniades and P. Pantazis, “Platelet-derived growth factor: purification and characterization,” Methods in Enzymology, vol. 169, pp. 210–224, 1989. View at Google Scholar · View at Scopus
  59. Z. K. Otrock, R. A. R. Mahfouz, J. A. Makarem, and A. I. Shamseddine, “Understanding the biology of angiogenesis: review of the most important molecular mechanisms,” Blood Cells, Molecules, and Diseases, vol. 39, no. 2, pp. 212–220, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. P. Lindblom, H. Gerhardt, S. Liebner et al., “Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall,” Genes and Development, vol. 17, no. 15, pp. 1835–1840, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Hellström, M. Kalén, P. Lindahl, A. Abramsson, and C. Betsholtz, “Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse,” Development, vol. 126, no. 14, pp. 3047–3055, 1999. View at Google Scholar · View at Scopus
  62. P. A. Campochiaro, S. F. Hackett, S. A. Vinores et al., “Platelet-derived growth factor is an autocrine growth stimulator in retinal pigmented epithelial cells,” Journal of Cell Science, vol. 107, no. 9, pp. 2459–2469, 1994. View at Google Scholar · View at Scopus
  63. H. Freyberger, M. Bröcker, H. Yakut et al., “Increased levels of platelet-derived growth factor in vitreous fluid of patients with proliferative diabetic retinopathy,” Experimental and Clinical Endocrinology and Diabetes, vol. 108, no. 2, pp. 106–109, 2000. View at Publisher · View at Google Scholar · View at Scopus
  64. T. Yokota, R. C. Ma, J. Y. Park et al., “Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes,” Diabetes, vol. 52, no. 3, pp. 838–845, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Javerzat, P. Auguste, and A. Bikfalvi, “The role of fibroblast growth factors in vascular development,” Trends in Molecular Medicine, vol. 8, no. 10, pp. 483–489, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. K. A. Thomas, “Fibroblast growth factors,” The FASEB Journal, vol. 1, no. 6, pp. 434–440, 1987. View at Google Scholar · View at Scopus
  67. M. Papetti and I. M. Herman, “Mechanisms of normal and tumor-derived angiogenesis,” American Journal of Physiology, vol. 282, no. 5, pp. C947–C970, 2002. View at Google Scholar · View at Scopus
  68. S. K. Kostyk, P. A. D'Amore, I. M. Herman, and J. A. Wagner, “Optic nerve injury alters basic fibroblast growth factor localization in the retina and optic tract,” Journal of Neuroscience, vol. 14, no. 3, part 2, pp. 1441–1449, 1994. View at Google Scholar · View at Scopus
  69. M. Ohsato, H. Hayashi, K. Oshima, T. Koji, and P. Nakane, “In situ localization of basic fibroblast growth factor protein and mRNA in the retina,” Ophthalmic Research, vol. 29, no. 1, pp. 24–30, 1997. View at Google Scholar · View at Scopus
  70. I. Grierson, L. Heathcote, P. Hiscott, P. Hogg, M. Briggs, and S. Hagan, “Hepatocyte growth factor/scatter factor in the eye,” Progress in Retinal and Eye Research, vol. 19, no. 6, pp. 779–802, 2000. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Bhargava, A. Joseph, J. Knesel et al., “Scatter factor and hepatocyte growth factor: activities, properties, and mechanism,” Cell Growth & Differentiation, vol. 3, no. 1, pp. 11–20, 1992. View at Google Scholar · View at Scopus
  72. M. Nishimura, T. Ikeda, M. Ushiyama, S. Kinoshita, and M. Yoshimura, “Changes in vitreous concentrations of human hepatocyte growth factor (hHGF) in proliferative diabetic retinopathy: implications for intraocular hHGF production,” Clinical Science, vol. 98, no. 1, pp. 9–14, 2000. View at Google Scholar · View at Scopus
  73. K. A. Houck, N. Ferrara, J. Winer, G. Cachianes, B. Li, and D. W. Leung, “The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA,” Molecular Endocrinology, vol. 5, no. 12, pp. 1806–1814, 1991. View at Google Scholar · View at Scopus
  74. E. Tischer, R. Mitchell, T. Hartman et al., “The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing,” Journal of Biological Chemistry, vol. 266, no. 18, pp. 11947–11954, 1991. View at Google Scholar · View at Scopus
  75. N. Ferrara, “Vascular endothelial growth factor: basic science and clinical progress,” Endocrine Reviews, vol. 25, no. 4, pp. 581–611, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Eichmann, C. Corbel, V. Nataf, P. Vaigot, C. Bréant, and N. M. Le Douarin, “Ligand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5141–5146, 1997. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Dimmeler, E. Dernbach, and A. M. Zeiher, “Phosphorylation of the endothelial nitric oxide synthase at Ser-1177 is required for VEGF-induced endothelial cell migration,” FEBS Letters, vol. 477, no. 3, pp. 258–262, 2000. View at Publisher · View at Google Scholar · View at Scopus
  78. H. P. Gerber, A. McMurtrey, J. Kowalski et al., “Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation,” Journal of Biological Chemistry, vol. 273, no. 46, pp. 30336–30343, 1998. View at Publisher · View at Google Scholar · View at Scopus
  79. D. T. Connolly, D. M. Heuvelman, R. Nelson et al., “Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis,” Journal of Clinical Investigation, vol. 84, no. 5, pp. 1470–1478, 1989. View at Google Scholar · View at Scopus
  80. K. Miyamoto, S. Khosrof, S. E. Bursell et al., “Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1),” American Journal of Pathology, vol. 156, no. 5, pp. 1733–1739, 2000. View at Google Scholar · View at Scopus
  81. A. M. A. El-Asrar, M. I. Nawaz, D. Kangave et al., “High-mobility group box-1 and biomarkers of inflammation in the vitreous from patients with proliferative diabetic retinopathy,” Molecular Vision, vol. 17, pp. 1829–1838, 2011. View at Google Scholar
  82. J. Wang, E. Xu, M. H. Elliott, M. Zhu, and Y. Z. Le, “Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage,” Diabetes, vol. 59, no. 9, pp. 2297–2305, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. Y. Dor, R. Porat, and E. Keshet, “Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis,” American Journal of Physiology, vol. 280, no. 6, pp. C1367–C1374, 2001. View at Google Scholar · View at Scopus
  84. G. L. Semenza, “Angiogenesis in ischemic and neoplastic disorders,” Annual Review of Medicine, vol. 54, pp. 17–28, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Shweiki, A. Itin, D. Soffer, and E. Keshet, “Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis,” Nature, vol. 359, no. 6398, pp. 843–845, 1992. View at Publisher · View at Google Scholar · View at Scopus
  86. G. L. Wang, B. H. Jiang, E. A. Rue, and G. L. Semenza, “Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 12, pp. 5510–5514, 1995. View at Publisher · View at Google Scholar · View at Scopus
  87. H. Kimura, A. Weisz, T. Ogura et al., “Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide,” Journal of Biological Chemistry, vol. 276, no. 3, pp. 2292–2298, 2001. View at Google Scholar · View at Scopus
  88. F. Nussenbaum and I. M. Herman, “Tumor angiogenesis: insights and innovations,” Journal of Oncology, vol. 2010, Article ID 132641, 24 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. L. P. Aiello, R. L. Avery, P. G. Arrigg et al., “Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders,” The New England Journal of Medicine, vol. 331, no. 22, pp. 1480–1487, 1994. View at Publisher · View at Google Scholar · View at Scopus
  90. S. Ishida, T. Usui, K. Yamashiro et al., “VEGF164 is proinflammatory in the diabetic retina,” Investigative Ophthalmology and Visual Science, vol. 44, no. 5, pp. 2155–2162, 2003. View at Publisher · View at Google Scholar
  91. C. Bell, E. Lynam, D. J. Landfair, N. Janjic, and M. E. Wiles, “Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro,” In Vitro Cellular and Developmental Biology—Animal, vol. 35, no. 9, pp. 533–542, 1999. View at Google Scholar · View at Scopus
  92. E. S. Gragoudas, A. P. Adamis, E. T. Cunningham, M. Feinsod, and D. R. Guyer, “Pegaptanib for neovascular age-related macular degeneration,” The New England Journal of Medicine, vol. 351, no. 27, pp. 2805–2816, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Holash, S. Davis, N. Papadopoulos et al., “VEGF-Trap: a VEGF blocker with potent antitumor effects,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 17, pp. 11393–11398, 2002. View at Publisher · View at Google Scholar · View at Scopus
  94. J. Gaudreault, D. Fei, J. Rusit, P. Suboc, and V. Shiu, “Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration,” Investigative Ophthalmology and Visual Science, vol. 46, no. 2, pp. 726–733, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. J. M. Rakic, V. Lambert, L. Devy et al., “Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization,” Investigative Ophthalmology and Visual Science, vol. 44, no. 7, pp. 3186–3193, 2003. View at Publisher · View at Google Scholar · View at Scopus
  96. B. P. Nicholson and A. P. Schachat, “A review of clinical trials of anti-VEGF agents for diabetic retinopathy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 248, no. 7, pp. 915–930, 2010. View at Publisher · View at Google Scholar · View at Scopus
  97. X. Fang, H. Sakaguchi, F. Gomi et al., “Efficacy and safety of one intravitreal injection of bevacizumab in diabetic macular oedema,” Acta Ophthalmologica, vol. 86, no. 7, pp. 800–805, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. Q. D. Nguyen, S. M. Shah, A. A. Khwaja et al., “Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study,” Ophthalmology, vol. 117, no. 11, pp. 2146–2151, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. M. Abouammoh and S. Sharma, “Ranibizumab versus bevacizumab for the treatment of neovascular age-related macular degeneration,” Current Opinion in Ophthalmology, vol. 22, no. 3, pp. 152–158, 2011. View at Publisher · View at Google Scholar
  100. A. Mirshahi, R. Roohipoor, A. Lashay, S. F. Mohammadi, A. Abdoallahi, and H. Faghihi, “Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial,” European Journal of Ophthalmology, vol. 18, no. 2, pp. 263–269, 2008. View at Google Scholar · View at Scopus
  101. D. V. Do, U. Schmidt-Erfurth, V. H. Gonzalez et al., “The da VINCI study: phase 2 primary results of VEGF trap-eye in patients with diabetic macular edema,” Ophthalmology, vol. 118, no. 9, pp. 1819–1826, 2011. View at Publisher · View at Google Scholar
  102. D. M. Brown, M. Michels, P. K. Kaiser, J. S. Heier, J. P. Sy, and T. Ianchulev, “Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study,” Ophthalmology, vol. 116, no. 1, pp. 57–65, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. P. K. Kaiser, D. M. Brown, K. Zhang et al., “Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results,” American Journal of Ophthalmology, vol. 144, no. 6, pp. 850–e4, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. J. S. Heier, D. S. Boyer, T. A. Ciulla et al., “Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS study,” Archives of Ophthalmology, vol. 124, no. 11, pp. 1532–1542, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. A. N. Antoszyk, L. Tuomi, C. Y. Chung, and A. Singh, “Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results,” American Journal of Ophthalmology, vol. 145, no. 5, pp. 862–e3, 2008. View at Publisher · View at Google Scholar · View at Scopus
  106. L. Wu, M. A. Martínez-Castellanos, H. Quiroz-Mercado et al., “Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the pan-american collaborative retina study group (PACORES),” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 1, pp. 81–87, 2008. View at Publisher · View at Google Scholar
  107. H. Hurwitz, L. Fehrenbacher, W. Novotny et al., “Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer,” The New England Journal of Medicine, vol. 350, no. 23, pp. 2335–2342, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. J. C. Yang, L. Haworth, R. M. Sherry et al., “A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer,” The New England Journal of Medicine, vol. 349, no. 5, pp. 427–434, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. F. A. Scappaticci, J. R. Skillings, S. N. Holden et al., “Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab,” Journal of the National Cancer Institute, vol. 99, no. 16, pp. 1232–1239, 2007. View at Publisher · View at Google Scholar · View at Scopus
  110. J. F. Arevalo, M. Maia, H. W. Flynn et al., “Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy,” British Journal of Ophthalmology, vol. 92, no. 2, pp. 213–216, 2008. View at Publisher · View at Google Scholar · View at Scopus
  111. S. Moradian, H. Ahmadieh, M. Malihi, M. Soheilian, M. H. Dehghan, and M. Azarmina, “Intravitreal bevacizumab in active progressive proliferative diabetic retinopathy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 12, pp. 1699–1705, 2008. View at Publisher · View at Google Scholar · View at Scopus
  112. O. Sawada, H. Kawamura, M. Kakinoki, T. Sawada, and M. Ohji, “Vascular endothelial growth factor in aqueous humor before and after intravitreal injection of bevacizumab in eyes with diabetic retinopathy,” Archives of Ophthalmology, vol. 125, no. 10, pp. 1363–1366, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. R. L. Avery, J. Pearlman, D. J. Pieramici et al., “Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy,” Ophthalmology, vol. 113, no. 10, pp. 1695–e1, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. R. W. Beck, A. R. Edwards, L. P. Aiello et al., “Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema,” Archives of Ophthalmology, vol. 127, no. 3, pp. 245–251, 2009. View at Publisher · View at Google Scholar
  115. J. A. Haller, B. D. Kuppermann, M. S. Blumenkranz et al., “Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema,” Archives of Ophthalmology, vol. 128, no. 3, pp. 289–296, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. E. Boscolo, C. L. Stewart, S. Greenberger et al., “JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 10, pp. 2181–2192, 2011. View at Publisher · View at Google Scholar
  117. J. T. Durham and I. M. Herman, “Microvascular modifications in diabetic retinopathy,” Current Diabetes Reports, vol. 11, no. 4, pp. 253–264, 2011. View at Publisher · View at Google Scholar
  118. A. Truong, T. Y. Wong, and L. M. Khachigian, “Emerging therapeutic approaches in the management of retinal angiogenesis and edema,” Journal of Molecular Medicine, pp. 1–19, 2010. View at Publisher · View at Google Scholar · View at Scopus