Female gender, estrogen loss, and Sub-RPE deposit formation in aged mice.
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.
Cousins, SW; Marin-Castaño, ME; Espinosa-Heidmann, DG; Alexandridou, A; Striker, L; Elliot, S
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