Abstract
Retinal neovascularization (NV) is a major cause of blindness in ischemic retinopathies. Previous investigations have indicated that ischemia upregulates GFAP and PDGF-B expression. GFAP overexpression is a hallmark of reactive gliosis (RG), which is the major pathophysiological feature of retinal damage. In addition, PDGF-B has been implicated in proliferative retinopathies. It was the aim of this study to gain insights on the possible pharmacological interventions to modulate PDGF-B and GFAP expression, and its influence on RG and NV. We used an array of assays to evaluate the effects of YC-1, a small molecule inhibitor of HIF-1 and a novel NO-independent activator of soluble guanylyl cyclase (sGC), on RG and NV, in vivo and in vitro. When compared to the DMSO-treated retinas, dual-intravitreal injections of YC-1, in vivo: (1) suppressed the development and elongation of neovascular sprouts in the retinas of the oxygen-induced retinopathy (OIR) mouse model; and (2) reduced ischemia-induced overexpression of GFAP and PDGF-B at the message (by 64.14±0.5% and 70.27±0.04%) and the protein levels (by 65.52±0.02% and 57.59±0.01%), respectively. In addition, at 100 µM, YC-1 treatment downregulated the hypoxia-induced overexpression of GFAP and PDGF-B at the message level in rMC-1 cells (by 71.42±0.02% and 75±0.03%), and R28 cells (by 58.62±0.02% and 50.00±0.02%), respectively; whereas, the protein levels of GFAP and PDGF-B were reduced (by 78.57±0.02% and 77.55±0.01%) in rMC-1cells, and (by 81.44±0.02% and 79.16±0.01%) in R28 cells, respectively. We demonstrate that YC-1 reversed RG during ischemic retinopathy via impairing the expression of GFAP and PDGF-B in glial cells. This is the first investigation that delves into the reversal of RG during ischemic retinal vasculopathies. In addition, the study reveals that YC-1 may exert promising therapeutic effects in the treatment of retinal and neuronal pathologies.
Highlights
Diabetic retinopathy [DR] is a leading cause of visual disturbance in adults and is the leading cause of blindness in Americans between the ages of 20 and 74 years [1]
In this study we have investigated the effects of YC-1, a small molecule inhibitor of hypoxia induced factor -1 (HIF-1), on experimentally induced retinopathy using the oxygen-induced retinopathy (OIR) mouse model
The OIR mouse model has been extensively used because it constitutes several clinical manifestations that are analogous to the retinopathy of maturity [ROP], and mimics the important aspects of PDR; the most common ischemic retinopathy in patients [43]
Summary
Diabetic retinopathy [DR] is a leading cause of visual disturbance in adults and is the leading cause of blindness in Americans between the ages of 20 and 74 years [1]. In the early non-proliferative stage, retinal vascular permeability can increase even before the appearance of clinical retinopathy [2] This stage is diagnosed by dilation of retinal veins, retinal microaneurysmas, intraretinal microvascular abnormalities, areas of capillary nonperfusion, retinal hemorrhages, cotton wool spots, edema, and exudates. New vessels can extend into the vitreous cavity of the eye and can hemorrhage into the vitreous, resulting in visual loss [3] They can cause tractional retinal detachments from the accompanying contractile fibrous tissue. During this stage, over-proliferation of capillary endothelial cells [ECs] results in retinal neovascularization [NV], abnormal formation of new vessels in the retina and the vitreous, leading to PDR [4]. Retinal edema involves the breakdown of the bloodretinal barrier, with leakage of plasma from small BVs
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