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I.A. Bhutto, K. Uno, C. Merges, D.S. McLeod, S. Ren, H. Lai, G.A. Lutty; Endogenous Inhibitors of Angiogenesis Are Decreased in the Submacular Region of Age–Related Macular Degeneration (AMD) Eyes . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4174.
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© ARVO (1962-2015); The Authors (2016-present)
Bruch's membrane (BM) is a stratified extracellular matrix complex that functions as a physical as well as biochemical barrier for normal physiologic processes and pathological processes like choroidal neovascularization (CNV). We have reported the expression and localization of endogenous inhibitors [pigment epithelium–derived factor (PEDF), endostatin, and thrombospondin–1 (TSP–1)] individually within the retinal pigment epithelial (RPE)/BM/choriocapillaris (CC) complex in macula of eyes with AMD. The purpose of this study was to collectively determine whether the relative levels of these potent inhibitors were significantly changed in each individual AMD subject or in eyes with AMD as a group.
Immunohistochemical analysis of TSP–1, endostatin and PEDF was performed on cryopreserved frozen sections from macular blocks of aged control donor eyes (n= 6; mean age 78.8 yrs) and eyes with AMD (n= 9; mean age 83.9 yrs). Pigment in RPE and choroidal melanocytes was bleached. Three independent masked observers scored the immunohistochemical reaction product (0–8). Mean scores from the aged control eyes and scores from eyes with AMD were analyzed by using a Generalized Estimating Equation (GEE) regression model.
In aged control eyes, immunoreactivity of all 3 inhibitors was observed intensely in RPE/BM/CC complex. In BM and RPE basal lamina (BL), compared to the control eyes, the immunoreactivity of all 3 inhibitors combined was significantly lower (p<0.0001, p=0.014, respectively). Further analysis performed on each inhibitor showed that in BM, endostatin, PEDF and TSP–1 of all AMD eyes was significantly lower (p=0.0291, p<0.0001, p<0.0001, respectively) compared to the control eyes. In CC, significant reduction was observed in endostatin and TSP–1 (p=0.0019, p=0.0029, respectively). However, in RPE–BL, such reduction was only observed in PEDF (p=0.0062).
These findings suggest that the potent endogenous inhibitors of angiogenesis constitutively expressed in BM may provide both a physical and biochemical barrier for CNV formation and progression. Reduced levels of all three endogenous inhibitors in BM of all AMD eyes may make BM vulnerable to the formation of CNV.
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