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VEGF-Dependent Conjunctivalization of the Corneal Surface

¹From the Massachussetts Eye and Ear Infirmary, the ³Department of Adult Oncology, Dana-Farber Cancer Institute, and the ⁴Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; the ²Department of Vitreoretinal Surgery, Center for Ophthalmology and Center for Molecular Medicine (ZMMK), University of Cologne, Cologne, Germany; the ⁵Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut; and ⁶Regeneron Pharmaceuticals, Inc., Tarrytown, New York.

PURPOSE. To investigate the mechanisms governing corneal neovascularization and the appearance of goblet cells in a murine model of limbal insufficiency.

METHODS. The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemical detection of the vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR1) was performed in paraffin-embedded sections. A transgenic mouse that expresses the reporter gene lacZ targeted to the Flt-1 locus through homologous recombination was used to analyze corneal expression of Flt-1. The presence of soluble and membranous goblet cell Flt-1 mRNA and protein content was assessed with Northern and Western blot analyses, respectively. Finally, systemic adenoviral expression of a soluble Flt-1/Fc construct was used to study the effect of inhibition of VEGF bioactivity on the appearance of goblet cells and neovascularization.

RESULTS. Corneal neovascularization preceded the appearance of goblet cells, although both processes overlapped temporally. Flt-1 was abundant in the conjunctiva-like epithelium covering the cornea, as well as in the goblet cells, invading leukocytes, and vasculature. A similar expression pattern was observed in the transgenic mice expressing the lacZ gene downstream from the Flt-1 promoter. Isolated human and rat goblet cells in culture expressed Flt-1 mRNA and protein, as did freshly isolated human conjunctiva. The systemic inhibition of VEGF bioactivity potently suppressed both corneal neovascularization (8.3% ± 8.1% vs. 41.1% ± 15.3% corneal area; P < 0.001) and corneal goblet cell density (1.6% ± 2.5% vs. 12.2% ± 2.4% corneal area; P < 0.001).

CONCLUSIONS. Two important features of corneal conjunctivalization, the appearance of goblet cells and neovascularization, are regulated by VEGF. Both processes are probably mediated, in part, through the Flt-1 receptor. Taken together, these data indicate that an anti-VEGF therapeutic approach may limit the visual loss associated with conjunctivalization of the corneal surface.

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