Genistein inhibited retinal neovascularization and expression of vascular endothelial growth factor and hypoxia inducible factor 1alpha in a mouse model of oxygen-induced retinopathy.
The effects of genistein on neovascularization, vascular endothelial growth factor (VEGF), and hypoxia inducible factor 1alpha (HIF1alpha) protein expression in a mouse model of oxygen-induced retinopathy were studied. The model of oxygen-induced retinal neovascularization was induced in newborn C57BL/6 mice by exposing 7-day-old mice to 75% oxygen for 5 days and then housing them in room air (relative hypoxia). Retinopathy was assessed by quantitation of vascular cell nuclei anterior to inner limiting membrane. Judged by relative fluorescence using a confocal scanning laser microscope coupled to a computer, VEGF and HIF1alpha protein expression were investigated. Genistein markedly inhibited the numbers of nuclei protruding above the inner limiting membrane under relative hypoxia conditions. The levels of nuclei numbers were suppressed by 50, 100, and 200 mg/kg body weight /day genistein to 87.4%, 72.0%, and 59.4%, respectively, compared to that untreated with genistein. VEGF protein was constitutively expressed in the preretinal area under normoxia conditions. Genistein markedly inhibited relative-hypoxia-elicited VEGF expression elevation in a dose-dependent manner. HIF1alpha expression was also observed in normoxia conditions. There was a 2.4-fold induction in preretinal HIF1alpha expression in oxygen-reared animals when compared to room-air-reared animals. Genistein dose-dependently suppressed HIF1alpha protein expression. These results indicated that the inhibition of VEGF and HIF1alpha protein expression by genistein may partly account for its effect on retinal neovascularization in vivo, and genistein could be an effective agent in the prevention and treatment of ocular neovascularization.
Wang
Bin
B
Department of Pharmacology, Nanjing Medical University, Nanjing, People's Republic of China. binwang@njmu.edu.cn
Zou
Ying
Y
Li
Hua
H
Yan
Hong
H
Pan
Jin-Shun
JS
Yuan
Zhi-Lan
ZL
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004195:Disease Models, Animal; D019833:Genistein / Q000627:therapeutic use*; D000860:Hypoxia / Q000150:complications; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010100:Oxygen / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014157:Transcription Factors / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D019833:Genistein; D010100:Oxygen