Reynolds, Jonathon

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eCommons at Roseman University

Vitamin C Reduces IGF-1 and VEGF Signaling in Retinal Endothelial CellsReynolds, Jonathon C.1; Turner, Elizabeth1; Alger, Tyler J.1; Islam, Nasif1; Manukyan, Varos V.1; Sheppert, Alexander P.1; Wang, Gaofeng2; Sant, David W.11. Noorda College of Osteopathic Medicine; 2. University of Miami Miller School of MedicineGlucose acts as a competitive inhibitor for vitamin C, an important cofactor for DNA methylation, when crossing the blood retinal barrier. The purpose is to investigate potential role of vitamin C in gene expression pathways that may lead to the development of diabetic retinopathy.Purpose• Primary, human retinal endothelial cells were treated either with or without 50 μM vitamin C.• RNA was extracted and RNA-seq was used to determine transcription changes.• Pathway analysis was performed using EnrichR, Gorilla, and Gene Set Enrichment Analysis (GSEA).MethodsAlthough the contribution of IGF-1 to diabetic retinopathy has been largely attributed to stimulation of production of vascular endothelial growth factor A (VEGFA) in retinal pigment epithelial cells (RPE), knockout of IGF-1 receptors in retinal vascular endothelial cells was shown to reduce neovascularization in an oxygen-induced retinopathy mouse model.  New blood vessels from proliferative diabetic retinopathy have been found to regress after anti-VEGF treatments, and anti-VEGF is similar in efficiency to panretinalphotocoagulation of the blood retinal barrier in diabetic retinopathy.ResultsLocal vitamin C deficiencies in the eyes of diabetics affect signaling in the retinal endothelial cells which may contribute to the breakdown of the blood-retinal barrier in diabetic retinopathy. ConclusionWorks Cited1. N. Cheung, P. Mitchell, T. Y. Wong. Diabetic retinopathy. Lancet. 2010. 376(9735):125-136.2. S. A. Vinores. Breakdown of the blood-retinal barrier. Encyclopedia of the eye. 2010. 2010:216-222.3. K. Hosoya, A. Minamizono, K. Katayama, T. Terasaki, M. Tomi. Invest Ophthalmol Vis Sci. 2004. 45(4):1232-1239.4. E. A. Minor, B. L. Court, J. I. Young, G. Wang. Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J Biol Chem. 2013. 288(19):13669-74.5. T. Kondo, D. Vicent, K. Suzuma et al. Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest. 2003. 111(12): 1835-1842.6. L. E. H. Smith, W. Shen, C. Perruzzi et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nature Medicine. 1999. 5:1390-1395. 7. Y. Zhao and R. P Singh. The role of anti-vascular endothelial growth factor (anti-VEGF) in the management of proliferative diabetic retinopathy. Drugs Context. 2018. 7:212532. Vitamin C regulates pathways related to diabetic retinopathy437 genes upregulated and 308 genes downregulated transcription after treatment with vitamin C. Several pathways that may contribute to the pathogenesis of diabetic retinopathy were down regulated including IGF-1 and VEGF signaling in retinal endothelial cells.DiscussionFigure 2. QuickGOflow-chart representing Gene Ontology pathway interactions involving terms related to leukocyte tethering or rolling.  Table 1. Table of pathways significantly downregulated in expression after treatment with vitamin c. All p-values are adjusted with the Banjamini-Hocherberg method. Figure 3. GSEA Traces from selected differential pathways.50 µM VitC0 µM VitCFigure 1. Heatmap showing the relative expression of differential genes. Red represents upregulated expression and blue represents downregulated expression. Figure 4. QuickGOflow-chart representing Gene Ontology pathway interactions involved with regulation of response to vascular endothelial growth factor A (VEGF-A).

Vitamin C Reduces IGF-1 and VEGF Signaling in Retinal Endothelial Cells

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Vitamin C Reduces IGF-1 and VEGF Signaling in Retinal Endothelial Cells

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