The role of estrogen for the etiology and treatment of intraocular inflammation and neovascularization

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We previously reported that estrogen increases the expression of VEGFR2 and VEGF in normoxia. Since estrogen often has protective features against pathologic ischemic conditions, we investigated the effects of estrogen on hypoxia-induced expression of VEGF in bovine retinal capillary endothelial cells (BRECs). We also studied how estrogen could modulate the gene expression of VEGF.Estrogen significantly reduced the hypoxia-induced VEGF mRNA at 9 and 24 hours under hypoxia. This inhibitory effect was dose-dependent between 10^<-9> M and 10^<-7> M, and tamoxifen reversed the effect. Gel shift assay showed that estrogen reduced hypoxia induced-binding of hypoxia inducible factor (HIF) to the VEGF promoter site, and estrogen reduced the expression of HIF-1α in dose-dependent manner (between 10^<-9> M and 10^<-7> M). These results indicate that E2 may reduce the hypoxia-induced VEGF mRNA expression through inhibiting the expression of HIF as well as the interaction of HIF with VEGF.This inh … More ibition may also be estrogen-receptor mediated. Since our results may imply that the effect of estrogen under hypoxia may differ from that in normoxia, we further investigated the effect of estrogen on retinopathy of prematurity (ROP) mouse model. Estrogen significantly reduced the avascular area induced by hyperoxia on postnatal day 12 (P12) and 19, and estrogen also reduced neovascularization on P19. These results indicate that estrogen may have a dual action on the expression of VEGF according to the different oxygen status. In a different series of experiments, we made laser-induced choroidal neovascularization (CNV) model in rats to study the sex preference in CNV formation. Fluorescein angiography showed that CNV formation induced by laser photocoagulation was more prominent in female rats than in male rats on day 7 and 14. Estrogen increased the expression of VEGFR-2 more in female rats and male rats with estrogen injection than in male rats 7 days after laser photocoagulation This study suggests some explanations for different susceptibility for CNV formation between two sexes. Less