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Y.-Z. Le, J. Guo, M. Zhu; Genetic Disruption of Müller Cell-Produced VEGF Does Not Affect Retinal Development and Integrity: Implication in Anti-VEGF Therapeutics. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5376.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in pathological neovascularization in diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller cell-produced VEGF was thought to be the major source of VEGF in retinal neovascularization in DR. To determine the role of Müller cell-produced VEGF in DR, we generated conditional VEGF knockout (KO) mice and defined the role of the Müller cell-produced VEGF in ischemia-induced retinal neovascularization, as reported in ARVO previously. For the up-coming ARVO, we also submitted separate abstracts describing the role of Müller cell-produced VEGF in ischemia-induced vascular leakage and diabetes-induced inflammation. The focus of this study is to discuss the role of the Müller cell-produced VEGF in the development and long-term integrity of the retina, which may have implications to anti-VEGF therapeutics for neovascularization in DR and AMD.
Conditional VEGF KO mice were generated by using floxed VEGF mice and our transgenic mice expressing Cre recombinase in Müller cells. VEGF expression was determined by Western blot analysis using extracts from dissected retina. Retinal morphology, function, and vasculature were examined by analysis of H&E stained retinal sections, ERG, angiography and vessel staining.
VEGF expression was significant reduced in the retina of the conditional VEGF KO mice. Retinal Morphology, function, and vasculature were normal in the conditional VEGF KO mice after early development. Ageing conditional VEGF KO mice subjected to normal environment or chemical hypoxia did not cause any significant changes in retinal morphology and function.
Our results suggest that Müller cell-produced VEGF may not be the source of VEGF for retinal development. In addition, genetic disruption of Müller cell-produced VEGF did not cause a detectable change in retinal morphology and function in mice under normal and hypoxic conditions, suggesting that a moderate reduction of VEGF by anti-VEGF agents, a major strategy to treat neovascularization in DR, is relatively safe.
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