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PJ Esser, AM Joussen, V Poulaki, SU Stechschulte, B Kirchhof, D Dart, GH Fong, SJ Wiegand, GD Yancopoulos, AP Adamis; VEGF-dependent Conjunctivalization of the Corneal Surface . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3165.
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Purpose:To investigate the mechanisms governing corneal neovascularization and conjunctivalization in a model of limbal insufficiency. Methods:In a murine model of limbal insufficiency and inflammatory angiogenesis, the spatial and time-dependent relationship between corneal neovascularization and goblet cell appearance was analyzed in corneal flat mounts and paraffin sections. Flt-1 expression was analyzed via Western blot, northern blot, immunohistochemistry, and in transgenic mice overexpressing lacZ targeted to the flt-1 locus through homologous recombination. VEGF inhibition, via systemic adenoviral soluble Flt-1 expression, was studied for its effects on corneal neovascularization and conjunctivalization. Results:Corneal neovascularization is temporally and spatially correlated with corneal goblet cell appearance. The expression of the VEGF receptor Flt-1 is markedly increased in the epithelium and invading leukocytes of the cornea. With the onset of corneal neovascularization, Flt-1 is also localized to vascular endothelial cells, as well as goblet cells in the epithelium. Isolated human and rat goblet cells also express Flt-1 mRNA and protein. The inhibition of VEGF activity via soluble Flt-1 reduced corneal vascularization (P< 0.05) and goblet cell invasion (P< 0.02). Conclusion:These results indicate that corneal conjunctivalization, including both goblet cell appearance and neovascularization, is regulated via VEGF. Goblet cells bear the Flt-1 receptor and appear in response to increased VEGF levels following limbal stem cell debridement. Thus anti-VEGF therapy may help restrict the development of pathological sequelae following limbal injury.
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