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D. G. Holt, M. Dixit, J. Simonis, B. K. Ambati; Characterization of Murine Models of Corneal Neovascularization Through Genome-Wide Microarray Expression Analysis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4627.
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Corneal neovascularization is a central feature in the pathogenesis of many blinding corneal disorders, and a major sight-threatening complication in corneal infections, chemical injury, and following keratoplasty, in which neovascularization adversely impacts corneal transplant survival. Our previous study demonstrated that the soluble form of VEGF receptor 1 (sFlt-1) is the main preserver of corneal avascularity. In an effort to identify additional biologic factors involved in the regulation of corneal avascularity, we have studied three different mouse strains, each of which exhibits a different propensity for corneal neovascularization. Importantly, the strains also differ in terms of corneal sFlt-1 expression. On one end of the spectrum, Pax6 heterozygous null mice develop spontaneous corneal neovascularization by four weeks of age, and have extremely low levels of corneal sFlt-1 expression. Wild-type C57/B6 mice (the parental strain for both Pax6+/- and MRL/MpJ strains) have avascular corneas that express high levels of sFlt-1, but develop neovascularization in response to corneal insult such as suture placement and alkali treatment. Finally, the MRL/MpJ strain, often termed the "healer" mouse, exhibits significant resistant to neovascularization following corneal trauma.
Utilizing RT-PCR, we found that corneas isolated from MRL/MpJ mice express supernormal levels of sFlt-1. These findings suggest that propensity toward corneal neovascularization is inversely correlated with sFlt-1 expression levels. It is likely that additional differentially expressed genes contribute to the observed differences in neovascular susceptibility found in these model strains. We have utilized an Agilent 44,000 spot microarray platform to analyze corneal gene expression on a genome-wide scale across this spectrum of mouse models.
Initial analysis of our microarray data has identified several differentially expressed genes. Novel candidates of specific interest include two proteinases, Adam17 and Mmp14, found to be upregulated in MRL/MpJ corneas. While previous work has not implicated these factors in the regulation of corneal vascularity, each is known to be directly involved in angiogenesis signaling pathways.
Further analysis of these and other differentially regulated genes identified in this study is likely to reveal significant insight into molecular pathways governing corneal vascularization.
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