Purpose: The Kimba mouse carries a human VEGF transgene which causes retinal neovascularisation similar to that seen in diabetic retinopathy. Here, we examine the relationship between differential gene expression induced by VEGF overexpression and the architectural changes that occur in the retinae of these mice. Methods: Retinal gene expression changes in juvenile and adult Kimba mice were assayed by microarray and compared to age-matched wt littermates. Transcription of selected genes was validated by qRT-PCR. Protein translation was determined using immunohistochemistry and ELISA. Results: Semaphorin 3C (Sema3C) was upregulated and the nuclear receptor Nr2e3 was downregulated in juvenile Kimba mice. Betacellulin (Btc) and endothelin-2 (Edn2) were upregulated in adults. Sema3C co-localised with glial fibrillary acidic protein (GFAP) in Muller cells of Kimba retinae at greater signal intensities than in wt. Edn2 was largely limited to the retinal ganglion cells of wt mice in both age-groups, but significant additional expression was evident in the photoreceptors of adult Kimba mice. Edn2 co-localised to Muller cell end-feet, and extended into the outer limiting membrane. Ednrb staining was most pronounced in the inner nuclear layer, the region containing Muller cell somata. Conclusions: An early spike in VEGF levels induced significant long-term retinal neovascularisation associated with changes to the retinal ganglion, photoreceptor and Muller cells. Overexpression of VEGF led to dysregulation of photoreceptor metabolism through differential expression of Nr2e3, Edn2, Btc and Sema3C. Alterations in the expression of these genes may therefore play key roles in the pathological mechanisms that result from retinal neovascularisation. (c) 2012 The Authors. Clinical and Experimental Ophthalmology (c) 2012 Royal Australian and New Zealand College of Ophthalmologists.