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

雌激素在眼内炎症和新生血管的病因和治疗中的作用

• 批准号: 11671735
• 负责人: MANDAI Michiko
• 金额: $ 2.37万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671735/
• 关键词: 17 beta estradiol; VEGF; choroidal neovascularization (CNV); vascular endothelial cell; VEGFR-2; retinopty of prematurity (ROP); 17 beta estradiol; 17beta-estradiol; ぶどう膜炎; 増殖

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

我们以前曾报道，在正常氧条件下，雌激素可增加VEGFR2和VEGF的表达。由于雌激素通常对病理性缺血条件具有保护作用，我们研究了雌激素对低氧诱导的牛视网膜毛细血管内皮细胞(BRECs)表达血管内皮生长因子的影响。此外，我们还研究了雌激素对血管内皮细胞生长因子基因表达的调节作用。在低氧后9小时和24小时，雌激素显著降低低氧诱导的血管内皮生长因子基因的表达。这种抑制作用在10^&lt；-9&gt；M和10^&lt；-7&gt；M之间呈剂量依赖关系，他莫昔芬能逆转这种抑制作用。凝胶漂移分析显示，雌激素可降低缺氧诱导的低氧诱导因子与血管内皮生长因子启动子的结合，并呈剂量依赖性地降低缺氧诱导因子-1α的表达(介于10^~(-9)~10^~(-7)~10~(-7)M之间)。这些结果表明，E2可能通过抑制缺氧诱导的血管内皮细胞生长因子的表达以及抑制缺氧诱导的血管内皮细胞生长因子与血管内皮生长因子的相互作用来减少缺氧诱导的血管内皮细胞生长因子的表达，从而抑制…更多的欲望也可能是由雌激素受体介导的。由于我们的结果可能暗示雌激素在低氧和常氧下的作用可能不同，因此我们进一步研究了雌激素对早产儿视网膜病变(ROP)小鼠模型的影响。在出生后第12天(P12)和第19天，雌激素显著减少高氧诱导的血管缺血区，并且在出生后第19天雌激素也减少了新生血管的形成。这些结果表明，雌激素可能根据氧状态的不同而对血管内皮细胞生长因子的表达具有双重作用。在不同的实验中，我们制作了激光诱导的大鼠脉络膜新生血管(CNV)模型，以研究CNV形成过程中的性别偏好。荧光血管造影术显示，在第7天和第14天，雌性大鼠的CNV形成比雄性大鼠更为明显。在激光光凝后第7天，雌性大鼠和注射雌激素的雄性大鼠比雄性大鼠更能增加VEGFR-2的表达。较少

项目成果

Suzuma I.Mandai M.Takagi H.Suzuma K.Otani A.Oh H.Kobayashi K.Honda Y: "17 Beta-estrdiol increases VEGF receptor-2 and promotes DNA synthesis in retinal microvascular endothelial cells."Invest Ophthalmol Vis Sci.. 40. 2122-2129 (1999)

Suzuma I.Mandai M.Takagi H.Suzuma K.Otani A.Oh H.Kobayashi K.Honda Y：“17 Beta-雌二醇可增加 VEGF 受体 2 并促进视网膜微血管内皮细胞中的 DNA 合成。”Invest Ophasemol Vis Sci。

Izumi Suzuma: "17 Beta-estradiol increases VEGF receptor-2 and promotes DNA synthesis in retinal microvascular endothelial cells"Invest-Ophthalmol-Vis-Sci.. 40(9). 2122-2129 (1999)

Izumi Suzuma：“17 Beta-雌二醇增加 VEGF 受体 2 并促进视网膜微血管内皮细胞中的 DNA 合成”Invest-Ophthalmol-Vis-Sci.. 40(9)。

Noriko Miyamoto: "Estrogen protects against cellular infiltration by reducing the expressions of E-selection and IL-6 in endotoxin-induced uveitis"J-Immunol.. 163(1). 374-379 (1999)

Noriko Miyamoto：“雌激素通过减少内毒素诱导的葡萄膜炎中 E-选择和 IL-6 的表达来防止细胞浸润”J-Immunol.. 163(1)。

Miyamoto N,Mandai M,Suzuma I,Suzuma K,Kobayashi K and Honda Y: "Estrogen protects against cellular infiltration by reducing the expressions of E-s electin and IL-6 in endotoxin-induced uveitis."The Journal of Immunology. 163. 374-379 (1999)

Miyamoto N、Mandai M、Suzuma I、Suzuma K、Kobayashi K 和 Honda Y：“雌激素通过减少内毒素诱导的葡萄膜炎中 E-s 选择素和 IL-6 的表达来防止细胞浸润。”《免疫学杂志》。

Miyamoto N.Mandai M.Suzuma I.Suzuma K.Kobayashi K and Honda Y: "Estrogen protects against cellular infiltration by reducing the expressions of E-s electin and IL-6 in endotoxin-induced uveitis."The Journal of Immunology. 163. 374-379 (1999)

Miyamoto N.Mandai M.Suzuma I.Suzuma K.Kobayashi K 和 Honda Y：“雌激素通过减少内毒素诱导的葡萄膜炎中 E-s 选择素和 IL-6 的表达来防止细胞浸润。”《免疫学杂志》。