title: NADPH oxidase 4-derived H2O2 promotes aberrant retinal neovascularization via activation of VEGF receptor 2 pathway in oxygen-induced retinopathy.
abstract: NADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidase in retinal endothelial cells. Our previous study suggests that upregulation of Nox4 in retinal endothelial cells contributes to retinal vascular leakage in diabetes. In the current study, we investigated the role and mechanism of Nox4 in regulation of retinal neovascularization (NV), a hallmark of proliferative diabetic retinopathy (PDR), using a mouse model of oxygen-induced retinopathy (OIR). Our results confirmed that Nox4 was expressed predominantly in retinal vasculature of mouse retina. Retinal expression of Nox4 was markedly increased in OIR, in parallel with enhanced phosphorylation of ERK. In human retinal microvascular endothelial cells (HRECs), overexpression of Nox4 by adenovirus significantly increased extracellular H2O2 generation, resulting in intensified VEGFR2 activation and exacerbated angiogenesis upon VEGF stimulation. In contrast, silencing Nox4 expression or scavenging H2O2 by polyethylene glycol- (PEG-) conjugated catalase inhibited endothelial migration, tube formation, and VEGF-induced activation of VEGFR2 signaling. Importantly, knockdown of retinal Nox4 by adenovirus-delivered siRNA significantly reduced ERK activation and attenuated retinal NV formation in OIR. Taken together, our data indicate that Nox4 promotes retinal NV formation through H2O2/VEGFR2/ERK signaling pathway. Reducing retinal Nox4 expression may represent a promising therapeutic approach for neovascular retinal diseases such as PDR.
authors: The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, 277 West Yanta Road, Xi'an, Shaanxi 710061, China ; Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA.
authors: Jingming
authors: J
authors: Li
authors: Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA ; Department of Ophthalmology & Ira G. Ross Eye Institute, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA ; SUNY Eye Institute, Buffalo, NY 14214, USA.
authors: Joshua J
authors: JJ
authors: Wang
authors: Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA ; Department of Ophthalmology & Ira G. Ross Eye Institute, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA ; SUNY Eye Institute, Buffalo, NY 14214, USA.
authors: Sarah X
authors: SX
authors: Zhang
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003930:Diabetic Retinopathy / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D051379:Mice; D008833:Microcirculation; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen