Abstract
Angiogenesis as a pathological process in the eye can lead to blindness. In the cornea, suppression of angiogenesis by anti-VEGF treatment is only partially effective while steroids, although effective in treating inflammation and angiogenesis, have broad activity leading to undesirable side effects. In this study, genome-wide expression was investigated in a suture-induced corneal neovascularization model in rats, to investigate factors differentially targeted by dexamethasone and anti-Vegf. Topical treatment with either rat-specific anti-Vegf, dexamethasone, or normal goat IgG (sham) was given to sutured corneas for 48 hours, after which in vivo imaging, tissue processing for RNA microarray, and immunofluorescence were performed. Dexamethasone suppressed limbal vasodilation (P < 0.01) and genes in PI3K-Akt, focal adhesion, and chemokine signaling pathways more effectively than anti-Vegf. The most differentially expressed genes were confirmed by immunofluorescence, qRTPCR and Western blot. Strong suppression of Reg3g and the inflammatory chemokines Ccl2 and Cxcl5 and activation of classical complement pathway factors C1r, C1s, C2, and C3 occurred with dexamethasone treatment, effects absent with anti-Vegf treatment. The genome-wide results obtained in this study provide numerous potential targets for specific blockade of inflammation and angiogenesis in the cornea not addressed by anti-Vegf treatment, as possible alternatives to broad-acting immunosuppressive therapy.
Highlights
Angiogenesis is an essential physiologic process occurring during embryogenesis as well as in adult organisms in the context of wound healing, muscle growth, and the menstrual cycle
Choroidal and retinal neovascularization can lead to blindness in wet age-related macular degeneration (AMD)[4], proliferative diabetic retinopathy[5], retinopathy of prematurity[6] and uveitis[7]
Vascular endothelial growth factor A (VEGFA) is secreted by corneal epithelium[10], infiltrating leukocytes[11,12,13], and vascular endothelial cells[14] and its expression is upregulated in the early phases of neovascularization[15]
Summary
Angiogenesis is an essential physiologic process occurring during embryogenesis as well as in adult organisms in the context of wound healing, muscle growth, and the menstrual cycle. Addressing the inflammatory component of the angiogenic response (as steroids do) but in a more targeted manner than steroids, may avoid side effects while potentially improving the efficacy of alternative treatments With this rationale in mind, we previously reported on a comparison of topical anti-Vegf treatment with steroids (topical dexamethasone) in a model of inflammatory neovascularization in the rat cornea[32]. The purpose of the present study was to investigate the active phase of inflammation preceding sprouting angiogenesis in the rat cornea, when both inflammatory and angiogenesis-related factor expression are naturally strong[33] During this early phase of inflammation, we performed genome-wide microarray analysis in anti-Vegf and dexamethasone-treated groups to systematically investigate the differential effect of these treatments at the gene expression level. The goal was to reveal candidate factors that could be targeted in the future to achieve a more effective suppression of inflammation and angiogenesis than is possible with anti-VEGF treatment, but in a more targeted manner than steroid therapy
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