Document Detail


Functional analyses of TNFR2 in physiological and pathological retina angiogenesis.
MedLine Citation:
PMID:  23188724     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: To determine the function of tumor necrosis factor receptor-2 (TNFR2) in retinal development and ischemia-induced revascularization in an oxygen-induced retinopathy (OIR) model.
METHODS: Mice with a global deletion of TNFR2 (TNFR2-KO) or with a vascular endothelial cell (EC)-specific TNFR2 transgene (TNFR2-TG) were compared to wild-type C57BL/6 mice (WT). Retinal vasculature development was visualized by whole-mount and cross-sectional isolectin staining. In the OIR model, neonatal mice were subjected to 75% oxygen from postnatal day (P)7 to P12 and then returned to normoxia from P12 to P17. Immunostaining and biochemical analyses were performed to assess the effects of TNFR2 deletion and TNFR2 transgenesis on retinal vascular repair.
RESULTS: TNFR2 deletion slightly delayed, while TNFR2 transgenesis weakly promoted, intraretinal vascular development and intraretinal vessel growth. TNFR2 deletion enhanced, while TNFR2 transgene reduced, hyperoxia-induced vaso-obliteration. However, hypoxia-induced revascularization and development of deep intraretinal vessels at P17 were reduced in TNFR2-KO but increased in TNFR2-TG mice without significant increase in preretinal neovascularization (NV). Moreover, TNFR2-TG/KO mice in which only vascular EC express TNFR2 sufficiently rescued the vascular defects of TNFR2-KO in the OIR model. Biochemical analyses of retina tissues showed that the phenotypic changes in retina correlated with TNFR2-dependent activation of Nuclear factor-κB (NF-κB) survival and bone marrow kinase (Bmx)-VEGFR2 angiogenic pathways.
CONCLUSIONS: TNFR2 plays a marginal role during retinal vascular development. TNFR2 in vascular EC strongly prevents hyperoxia-induced vaso-obliteration by inhibiting cell apoptosis, and promotes retinal repair by enhancing hypoxia-induced revascularization without increasing pathological neovascular tufts. Therefore, activation of TNFR2 signaling may be an ideal strategy for the treatment of OIR.
Authors:
Ting Wan; Zhe Xu; Huanjiao Jenny Zhou; Haifeng Zhang; Yan Luo; Yonghao Li; Wang Min
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  54     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-10     Completed Date:  2013-03-12     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  211-21     Citation Subset:  IM    
Affiliation:
Eye Center, Affiliated Second Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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MeSH Terms
Descriptor/Qualifier:
Angiopoietin-2 / genetics
Animals
Animals, Newborn
Anoxia / metabolism
Cell Survival
Disease Models, Animal
Endothelium, Vascular / metabolism
Epithelial Cells / cytology,  metabolism
Gene Expression
Humans
Infant, Newborn
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
NF-kappa B / metabolism
Neovascularization, Pathologic
Oxygen / adverse effects
Protein-Tyrosine Kinases / genetics
Receptor, TIE-2 / genetics
Receptors, Tumor Necrosis Factor, Type II / deficiency,  genetics,  metabolism*
Retina / pathology
Retinal Neovascularization / metabolism*
Retinopathy of Prematurity / metabolism*
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Grant Support
ID/Acronym/Agency:
R0 HL085789/HL/NHLBI NIH HHS; R01 HL109420/HL/NHLBI NIH HHS; R01HL065978/HL/NHLBI NIH HHS; R01HL109420/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Angiopoietin-2; 0/NF-kappa B; 0/Receptors, Tumor Necrosis Factor, Type II; 7782-44-7/Oxygen; EC 2.7.1.-/Bmx protein, mouse; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, TIE-2; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2
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