University of Heidelberg
Faculty of Medicine Mannheim
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Angiopoietin-1 is regulated by miR-204 and contributes to corneal neovascularization in KLEIP deficient mice

J. Kather, J. Friedrich, N. Woik, C. Sticht, N. Gretz, H. Hammes and J. Kroll

Invest Ophthalmol Vis Sci, 55, pp.4295-4303

Purpose: Corneal neovascularisation can cause loss of vision. The introduction of anti-VEGF therapy has been a major improvement of therapeutic options. Recently, we established Kelch-like Ect2-interacting protein (KLEIP) knockout mice as a model of spontaneous corneal neovascular dystrophy. The aim of the present study was to characterize corneal neovascularisation in progressive corneal dystrophy in KLEIP-/- mice, to evaluate the efficacy of anti-VEGF therapy and to identify novel molecular regulators in this experimental model. Methods: Corneal neovascularisation was assessed by immunohistochemistry. VEGF signalling was inhibited by injection of a blocking antibody. Microarrays were used to measure expression of mRNA and miRNA in dystrophic corneae. Results were validated by IHC and Western blotting. Results: Blood vessels and lymphatics grew from the limbus towards the dystrophic epithelium in corneae of KLEIP-/- mice. Blocking VEGF signalling did not reduce phenotype progression. Correspondingly, microarray analysis revealed no upregulation of canonical vascular growth factors in late dystrophy. During phenotype progression, angiopoietin-1 expression increased while miR-204 expression decreased. Bioinformatical analysis identified a binding site for miR-204 in the angiopoietin-1 gene. Validation by in vitro experiments confirmed regulation of angiopoietin-1 by miR-204. Conclusion: VEGF does not act as a major player in corneal neovascularisation in KLEIP-/- mice. However, the pro-angiogenic factor angiopoietin-1 was strongly upregulated in late stage phenotype, correlating with loss of miR-204 expression. Correspondingly, we identified miR-204 as a novel regulator of angiopoietin-1 in vitro. These findings may explain the incomplete efficacy of anti-VEGF therapy in the clinic and may provide new candidates for pharmaceutical intervention.

Contact: Dr. Frank Zöllner last modified: 21.09.2020
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