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W-H Xiao, R Zimmerman, E Wawrousek, SA Vinores; Upregulation of Vascular Endothelial Growth Factor (VEGF) Associated with Interleukin-1ß (IL-1ß) Expression and Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1267.
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Purpose: Transgenic mice that overexpress IL-1ß in the lens were used to determine whether neovascularization (NV) and increased vascular permeability associated with IL-1ß are mediated through an upregulation of VEGF. Methods: IL-1ß transgenic mice, normal mice, and mice undergoing retinal degeneration were stained for VEGF, albumin (to assess location and extent of blood-retinal barrier [BRB] breakdown), and Griffonia simplicifolia isolectin-B4 (GSA; to determine origin and extent of NV) at time points ranging from postnatal day 5 (P5) to adult. Results: IL-1ß transgenic mice develop intense VEGF immunoreactivity throughout the retina at P5-7, just after the onset of inflammatory cell infiltration, and a second peak of VEGF upregulation beginning at P15, coinciding with significant retinal destruction due to massive inflammation. The onset of BRB breakdown coincided with the upregulation of VEGF at P5-7 and widespread BRB breakdown was demonstrated from P9. From P9-12, aggregates of GSA-positive cells formed on the retinal surface. These cells migrated into the retina at P12-15 with the more superficial cells forming a network of vessels and the deeper cells remaining in small clusters, thus demonstrating that NV occurs much later than BRB breakdown. Homozygous FVB/N mice, which undergo retinal degeneration beginning at about P9, also demonstrate the latter peak of VEGF upregulation and the accompanying BRB breakdown, but not the early upregulation. VEGF immunostaining was neutralized by pre-incubation with VEGF peptide. Non-transgenic mice did not develop NV. Conclusion: The early peak of VEGF upregulation (P5-7) appears to be due to IL-1ß expression and is likely to be dependent on inflammatory cell infiltration. The latter peak appears to be related to retinal destruction.
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