title: TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization.
abstract: OBJECTIVE
  Retinal neovascularization (NV) is a major cause of vision loss in ischemia-induced retinopathy. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor inducible-14 (Fn14), have been implicated in angiogenesis, but their role in retinal diseases is unknown. The goal of this study was to investigate the role of TWEAK/Fn14 pathway in retinal NV.
  
  
  METHODS
  Studies were performed in a mouse model of oxygen-induced retinopathy (OIR) and in primary human retinal microvascular endothelial cells (HRMECs). Hyperoxia treatment was initiated on postnatal day (P)14. Immunohistochemistry and quantitative PCR (qPCR) were used to assess retinal vascular changes in relation to expression of Fn14 and TWEAK.
  
  
  RESULTS
  Fibroblast growth factor-inducible 14 mRNA was prominently increased from P13 to P17 in OIR retinas, whereas TWEAK level was slightly decreased. These alterations were normalized by hyperoxia treatment and were more striking in isolated retinal vessels. There was a discernible shift in the immunoreactivity of Fn14 and TWEAK from the neuronal layers in the healthy retina to the neovascular tufts in that of OIR. Blockade of TWEAK/Fn14 significantly prevented retinal NV while slightly accelerated revascularization. In contrast, activation of Fn14 positively regulated survival pathways in the B-cell lymphoma-2 (Bcl2) family and robustly enhanced HRMEC survival. Furthermore, gene analysis revealed the regulatory region of Fn14 gene contains several conserved hypoxia inducible factor (HIF)-1α binding sites. Overexpression of HIF-1α prominently induced Fn14 expression in HRMECs.
  
  
  CONCLUSIONS
  We found that the TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible-14 (Fn14) pathway is involved in the development of pathologic retinal neovascularization. Hypoxia inducible factor-1α is likely implicated in the upregulation of Fn14.
authors.affiliation: Department of Ophthalmology and Visual Sciences, the University of Texas Medical Branch, Galveston, Texas.
authors.forename: Hossein
authors.initials: H
authors.lastname: Ameri
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Yonju
authors.initials: Y
authors.lastname: Ha
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Paulucci-Holthauzen
authors.forename: Shuqun
authors.initials: S
authors.lastname: Hu
authors.forename: Massoud
authors.initials: M
authors.lastname: Motamedi
authors.forename: Bernard F
authors.initials: BF
authors.lastname: Godley
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tilton
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012171:Retinal Vessels / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D000074050:TWEAK Receptor; D014162:Transfection; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000235:genetics*
chemical_list: D000074049:Cytokine TWEAK; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors
keywords: Fn14; TWEAK; ischemia-induced retinopathy; neovascularization; retina