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Despite intensive effort in the field, the cellular mechanisms of VEGF action remain virtually uninvestigated. This situation makes it difficult to design cellular target\u2010based therapeutics for these diseases. In light of the recent finding that VEGF is a potential neurotrophic factor, revealing the cellular mechanisms of VEGF action becomes necessary to preserve its beneficial effect and inhibit its pathological function in long\u2010term anti\u2010VEGF therapeutics for ocular vascular diseases. We therefore generated conditional VEGF knockout mice with an inducible Cre\/\n                    <jats:italic>lox<\/jats:italic>\n                    system and determined the significance of M\u00fcller cell\u2010derived VEGF in retinal development and maintenance and ischaemia\u2010induced neovascularizartion and vascular leakage. Retinal development in the conditional VEGF knockout mice was analysed by examining retinal and choroidal vasculatures and retinal morphology and function. Ischaemia\u2010induced retinal neovascularization and vascular leakage in the conditional VEGF knockout mice were analysed with fluorescein angiography, quantification of proliferative neovascular cells, immunohistochemistry, and immunoblotting using an oxygen\u2010induced retinopathy model. Our results demonstrated that disruption of M\u00fcller cell\u2010derived VEGF resulted in no apparent defects in retinal and choroidal vasculatures and retinal morphology and function, significant inhibition of the ischaemia\u2010induced retinal neovascularization and vascular leakage, and attenuation of the ischaemia\u2010induced breakdown of the blood\u2010retina barrier. These results suggest that the retinal M\u00fcller cell\u2010derived VEGF is a major contributor to ischaemia\u2010induced retinal vascular leakage and pre\u2010retinal and intra\u2010retinal neovascularization. The observation that a significant, but not complete, reduction of VEGF in the retina does not cause detectable retinal degeneration suggests that appropriate doses of anti\u2010VEGF agents may be important to the safe treatment of retinal vascular diseases. Copyright \u00a9 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.\n                  <\/jats:p>","DOI":"10.1002\/path.2611","type":"journal-article","created":{"date-parts":[[2009,8,11]],"date-time":"2009-08-11T13:00:18Z","timestamp":1249995618000},"page":"446-454","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":189,"title":["M\u00fcller cell\u2010derived VEGF is a significant contributor to retinal 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