title: Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy.
abstract: Revascularization of ischemic tissue is a highly desirable outcome in multiple diseases, including cardiovascular diseases and ischemic retinopathies. Oxidative stress and inflammation are both known to play a role in suppressing reparative angiogenesis in ischemic disease models including oxygen-induced retinopathy (OIR), but the regulatory molecules governing these pathophysiologic processes in retinal ischemia are largely unknown. Nrf2 is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis in the retina and other tissue beds. Using Nrf2-deficient mice, we investigated the effects of Nrf2 in regulating revascularization and modulating the retinal tissue milieu during ischemia. Strikingly, Nrf2's beneficial effect on reparative angiogenesis only became manifested in the later phase of ischemia in OIR, from postnatal day 14 (P14) to P17. This was temporally associated with a reduction in both oxidative stress and inflammatory mediators in wild-type compared to Nrf2-/-mice. Nrf2-/-retinas exhibited an increase in VEGF but also induction of anti-angiogenic Dll4/Notch signaling. NADPH oxidase (NOX), and especially NOX2, is a major pathogenic molecule and a particularly important contributor to oxidative stress in multiple retinal disease processes. Nrf2-/-mice exhibited a significant exacerbation of NOX2 induction in OIR that manifested in the later phases of ischemia. Pharmacologic inhibition of NADPH oxidase abrogated the adverse effect of Nrf2 deficiency on reparative angiogenesis. Taken together, this suggests that Nrf2 is an important regulator of the retinal milieu during tissue ischemia, and that the Nrf2/NOX2 balance may play a critical role in determining the fate of ischemic revascularization.
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Yanhong
authors: Y
authors: Wei
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Junsong
authors: J
authors: Gong
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Zhenhua
authors: Z
authors: Xu
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: eduh@jhmi.edu.
authors: Elia J
authors: EJ
authors: Duh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2 / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010100:Oxygen / Q000009:adverse effects*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012173:Retinitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D010100:Oxygen
keywords: Angiogenesis; Inflammation; Ischemia; NADPH oxidase; Nrf2; Oxidative stress