title: Inhibition of reactive gliosis prevents neovascular growth in the mouse model of oxygen-induced retinopathy.
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-1 cells, 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.
authors.affiliation: Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. mdeniro@kkesh.med.sa
authors.forename: Michael
authors.initials: M
authors.lastname: DeNiro
authors.forename: Falah H
authors.initials: FH
authors.lastname: Al-Mohanna
authors.forename: Futwan A
authors.initials: FA
authors.lastname: Al-Mohanna
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000009:adverse effects*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D012164:Retinal Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005663:Furans; D005904:Glial Fibrillary Acidic Protein; D051793:Hypoxia-Inducible Factor 1; D007191:Indazoles; D009419:Nerve Tissue Proteins; D020574:Proto-Oncogene Proteins c-sis; C528900:glial fibrillary astrocytic protein, mouse; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D010100:Oxygen