Pathological but not physiological retinal neovascularization is altered in TNF-Rp55-receptor-deficient mice.
OBJECTIVE
Tumor necrosis factor (TNF)-alpha is one of the major cytokines in inflammation and apoptosis. It has been demonstrated that inhibition of TNFalpha can reduce leukocyte adhesion, vascular leakage, and apoptotic endothelial cell death in diabetes. This study was conducted to investigate the effect of TNF-Rp55 and TNF-Rp75 on retinal development in oxygen-induced retinopathy.


METHODS
TNF-Rp55- and TNF-Rp75-deficient mice, as well as their respective wild-type controls, were exposed to 75% oxygen from postnatal day P7 to P12. Retinal vascularization was investigated in flatmount preparations after concanavalin A labeling of endothelial cells on days P6, P14, P17, and P20. Retinal mRNA expression of VEGF, angiopoietin-1 and -2, and PDGF was examined at days P14 and P20.


RESULTS
TNF-Rp55- and TNF-Rp75-deficient mice demonstrated similar retinal development and vascularization under normoxic conditions. In comparison to wild-type mice, the vascularized area remained stable during the observation time, although the gene expression of VEGF, angiopoietin (ang)-1 and -2, and PDGFb changed. Compared with that in the wild type mice, the relative expression of VEGF, ang-1, ang-2, and PDGFb changed 5.14-, 1.7-, 0.39-, and 0.36-fold in Rp55(-/-) mice and 4.1-, 9.5 x 10(-5)-, 0.12-, and 2975-fold in Rp75(-/-) mice, respectively. Treatment with oxygen resulted in a significantly reduced vascularization in Rp55(-/-) but not Rp75(-/-) mice on postnatal day (P)20.


CONCLUSIONS
Inhibition of TNFalpha via TNF-Rp55 can alter retinal development and angiogenesis in a model of oxygen-induced retinopathy. The data underscore the potential effectiveness of TNF-inhibitory treatments as modulators in oxygen-induced retinopathy.
Kociok
Norbert
N
Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, Cologne, Germany.
Radetzky
Sven
S
Krohne
Tim U
TU
Gavranic
Claudia
C
Joussen
Antonia M
AM
D042683:Angiopoietin-1 / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000633:toxicity; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000139:chemically induced; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D042683:Angiopoietin-1; C467629:Angpt1 protein, rat; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C069521:recombinant human tumor necrosis factor-binding protein-1; D010100:Oxygen