Female gender, estrogen loss, and sub-RPE deposit formation in aged mice
Female gender, estrogen loss, and sub-RPE deposit formation in aged mice
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DOI：
10.1167/iovs.02-0285
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发表时间：
2003-03-01
影响因子：
4.4
通讯作者：
Elliot, S
中科院分区：
文献类型：
--
作者：
Cousins, SW;Marin-Castaño, ME;Elliot, S
目的。雌激素水平影响妇女许多疾病的发病率和严重程度。由于绝经期提前的女性出现更严重的ARMD风险，雌激素缺乏也可能导致女性ARMD的发病或严重程度。研究发现，饲喂高脂肪饮食并短暂暴露于蓝绿光下的老年雄性C57BL/6小鼠表现出显著的亚rpe沉积和轻度Bruch膜增厚。该模型旨在描述性别和雌激素水平在该模型中的作用。9、16月龄的C57BL/6雌雄小鼠分别饲喂高脂饲料4.5个月。几组9个月大的雌性小鼠通过卵巢切除术，添加或不添加外源性17 - β -雌二醇来消耗雌激素。在高脂肪饮食4周后，眼睛在2周内暴露在7次5秒剂量的无光毒性蓝绿色光下。停止蓝光治疗三个半月后，通过透射电子显微镜评估沉积物的严重程度、BrM变化和绒毛膜内皮形态。在一些小鼠中，对新鲜分离的RPE蛋白提取物进行明胶酶谱分析和Western blot分析，以确定雌激素对RPE中基质金属蛋白酶(MMP)-2活性的影响。雄性和雌性16月龄小鼠的基底层流沉积形态在质量上相似，但雌性小鼠的厚度、连续性和含量的严重程度明显大于雌性小鼠。与年龄匹配的雄性小鼠相比，老年雌性小鼠也表现出更严重的内皮改变和BrM增厚的趋势。切除卵巢的中年小鼠比假手术对照组小鼠显示出更严重的沉积物。然而，接受高剂量雌激素补充的卵巢切除小鼠也显示出显著的沉积，尽管它们的BrMs比雌激素缺乏的小鼠更薄。RPE MMP-2活性的丧失与沉积严重程度相关，雌激素缺乏小鼠表达的MMP-2少于卵巢完整对照组小鼠。老年小鼠的雌性和中年小鼠的雌激素缺乏似乎会增加亚rpe沉积形成的严重程度。雌激素缺乏可能通过失调BrM的周转，增加亚rpe沉积形成的易感性，导致胶原增厚和内皮改变。在本研究中使用的剂量下补充雌激素似乎不能防止亚rpe沉积物的形成。
PURPOSE. Estrogen status influences the incidence and severity of many diseases in women. Because women with early menopause appear at risk for worse ARMD, estrogen deficiency may also contribute to the onset or severity of ARMD in women. It has been observed that aged male C57BL/6 mice fed a high-fat diet and briefly exposed to blue-green light exhibit development of significant sub-RPE deposits and mild Bruch's membrane (BrM) thickening. This model was used in an attempt to delineate the role of gender and estrogen status in this model.METHODS. C57BL/6 male and female mice of 9 or 16 months were fed a high-fat diet for 4.5 months. Several groups of 9-month-old female mice underwent estrogen depletion by ovariectomy, with or without supplementation with exogenous 17beta-estradiol. After 4 weeks of a high-fat diet, the eyes were exposed to seven 5-second doses of nonphototoxic levels of blue-green light over 2 weeks. Three and a half months after cessation of blue light treatment, transmission electron microscopy was performed to assess severity of deposits, BrM changes, and choriocapillaris endothelial morphology. In some,mice, gelatin zymography and Western blot analyses were performed on protein extracts of freshly isolated RPE to determine the effect of estrogen on matrix metalloproteinase (MMP)-2 activity in the RPE.RESULTS. Both male and female 16-month-old mice showed qualitatively similar basal laminar deposit morphology, but the severity of thickness, continuity, and content was significantly greater in female mice. Aged female mice also demonstrated a trend toward more severe endothelial changes and increased BrM thickening compared with age-matched male mice. Ovariectomized middle-aged mice showed more severe deposits than sham-surgery control animals. However, ovariectomized mice that received high-dose estrogen supplementation also showed significant deposits, although they had thinner BrMs than did the estrogen-deficient mice. Loss of RPE MMP-2 activity correlated with deposit severity, with estrogen-deficient mice expressing less MMP-2 than ovary-intact control mice.CONCLUSIONS. Female gender in aged mice and estrogen deficiency in middle-aged mice appears to increase the severity of sub-RPE deposit formation. Estrogen deficiency may increase susceptibility to formation of sub-RPE deposits by dysregulating turnover of BrM, contributing to collagenous thickening and endothelial changes. Estrogen supplementation at the dosages used in this study does not appear to protect against formation of sub-RPE deposits.