Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model
Tóm tắt
Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time. Human VEGF165 (hVEGF165) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified. trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF165 upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases. The data suggest that even an early short-term elevation in hVEGF165 expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.
Tài liệu tham khảo
Aiello LP, Gardner TW, King GL et al (1998) Diabetic retinopathy. Diabetes Care 21:143–156
Fong DS, Aiello LP, Ferris FL 3rd, Klein R (2004) Diabetic retinopathy. Diabetes Care 27:2540–2553
Campochiaro PA (2000) Retinal and choroidal neovascularization. J Cell Physiol 184:301–310
Frank RN (2004) Diabetic retinopathy. N Engl J Med 350:48–58
Joussen AM, Murata T, Tsujikawa A, Kirchhof B, Bursell SE, Adamis AP (2001) Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 158:147–152
Miyamoto K, Khosrof S, Bursell SE et al (1999) Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA 96:10836–10841
Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA (2002) Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 133:373–385
Forsythe JA, Jiang BH, Iyer NV et al (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613
Adamis AP, Miller JW, Bernal MT et al (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445–450
Miller JW, Adamis AP, Aiello LP (1997) Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. Diabetes Metab Rev 13:37–50
Tolentino MJ, Adamis AP (1998) Angiogenic factors in the development of diabetic iris neovascularization and retinopathy. Int Ophthalmol Clin 38:77–94
Amin RH, Frank RN, Kennedy A, Eliott D, Puklin JE, Abrams GW (1997) Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 38:36–47
Aiello LP, Bursell SE, Clermont A et al (1997) Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 46:1473–1480
Barber AJ, Antonetti DA (2003) Mapping the blood vessels with paracellular permeability in the retinas of diabetic rats. Invest Ophthalmol Vis Sci 44:5410–5416
Gilbert RE, Kelly DJ, Cox AJ et al (2000) Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes. Diabetologia 43:1360–1367
Ishida S, Usui T, Yamashiro K et al (2003) VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 44:2155–2162
Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, Inomata H (1995) Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Res 27:48–52
Qaum T, Xu Q, Joussen AM et al (2001) VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 42:2408–2413
Ozaki H, Hayashi H, Vinores SA, Moromizato Y, Campochiaro PA, Oshima K (1997) Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 64:505–517
Ohno-Matsui K, Hirose A, Yamamoto S et al (2002) Inducible expression of vascular endothelial growth factor in adult mice causes severe proliferative retinopathy and retinal detachment. Am J Pathol 160:711–719
Okamoto N, Tobe T, Hackett SF et al (1997) Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 151:281–291
Tobe T, Okamoto N, Vinores MA et al (1998) Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 39:180–188
Lai CM, Dunlop SA, May LA et al (2005) Generation of transgenic mice with mild and severe retinal neovascularisation. Br J Ophthalmol 89:911–916
Binz N, Graham CE, Simpson K et al (2006) Long-term effect of therapeutic laser photocoagulation on gene expression in the eye. Faseb J 20:383–385
Shen WY, Yu MJ, Barry CJ, Constable IJ, Rakoczy PE (1998) Expression of cell adhesion molecules and vascular endothelial growth factor in experimental choroidal neovascularisation in the rat. Br J Ophthalmol 82:1063–1071
Guidolin D, Vacca A, Nussdorfer GG, Ribatti D (2004) A new image analysis method based on topological and fractal parameters to evaluate the angiostatic activity of docetaxel by using the Matrigel assay in vitro. Microvasc Res 67:117–124
Abramoff M, Magalhaes P, Ram S (2004) Image processing with ImageJ. Biophoton Int 11:36–42
Su EN, Alder VA, Yu DY, Yu PK, Cringle SJ, Yogesan K (2000) Continued progression of retinopathy despite spontaneous recovery to normoglycemia in a long-term study of streptozotocin-induced diabetes in rats. Graefes Arch Clin Exp Ophthalmol 238:163–173
Kuwabara T, Cogan DG (1960) Studies of retinal vascular patterns. I. Normal architecture. Arch Ophthalmol 64:904–911
Ruberte J, Ayuso E, Navarro M et al (2004) Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J Clin Invest 113:1149–1157
Gao G, Li Y, Gee S et al (2002) Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5. J Biol Chem 277:9492–9497
Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J (2001) Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett 489:270–276
Stellmach V, Crawford SE, Zhou W, Bouck N (2001) Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc Natl Acad Sci USA 98:2593–2597
Ham DI, Kim SJ, Chen J et al (2004) Central immunotolerance in transgenic mice expressing a foreign antigen under control of the rhodopsin promoter. Invest Ophthalmol Vis Sci 45:857–862
Lebherz C, Maguire AM, Auricchio A et al (2005) Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factor. Diabetes 54:1141–1149
Lebherz C, Auricchio A, Maguire AM et al (2005) Long-term inducible gene expression in the eye via adeno-associated virus gene transfer in nonhuman primates. Hum Gene Ther 16:178–186
Rakoczy PE, Brankov M, Fonceca A, Zaknich T, Rae BC, Lai CM (2003) Enhanced recombinant adeno-associated virus-mediated vascular endothelial growth factor expression in the adult mouse retina: a potential model for diabetic retinopathy. Diabetes 52:857–863
No authors listed (1981) Diabetic retinopathy study. Report Number 6. Design, methods, and baseline results. Report Number 7. A modification of the Airlie House classification of diabetic retinopathy. Prepared by the Diabetic Retinopathy. Invest Ophthalmol Vis Sci 21:1–226
Antonetti DA, Lieth E, Barber AJ, Gardner TW (1999) Molecular mechanisms of vascular permeability in diabetic retinopathy. Semin Ophthalmol 14:240–248
Cunha-Vaz J, Bernardes R (2005) Nonproliferative retinopathy in diabetes type 2. Initial stages and characterization of phenotypes. Prog Retin Eye Res 24:355–377
Hellstedt T, Immonen I (1996) Disappearance and formation rates of microaneurysms in early diabetic retinopathy. Br J Ophthalmol 80:135–139
Caldwell RB, Bartoli M, Behzadian MA et al (2003) Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 19:442–455
Joussen AM, Poulaki V, Le ML et al (2004) A central role for inflammation in the pathogenesis of diabetic retinopathy. Faseb J 18:1450–1452
Joussen AM, Poulaki V, Qin W et al (2002) 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 160:501–509
Early Treatment Diabetic Retinopathy Study Research Group (1991) Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology 98:786–806
Dosso AA, Rungger-Brandle E, Leuenberger PM (2004) Ultrastructural alterations in capillaries of the diabetic hypertensive rat retina: protective effects of ACE inhibition. Diabetologia 47:1196–1201
Barber AJ (2003) A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry 27:283–290
Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW (2002) Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 47(Suppl 2):S253–S262
Ramsay RC, Goetz FC, Sutherland DE et al (1988) Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 318:208–214
No authors listed (1998) Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 116:874–886