Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 8, Pages 3012-3023Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI63816
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Funding
- Visual Sciences Research Center Core Facility [P30 EY11373]
- NIH [EY018383]
- Visual Sciences Training Program [T32 EY07157]
- Veterans Administration Office of Research and Development
- Ohio Lions Eye Research Foundation
- Foundation Fighting Blindness
- Research to Prevent Blindness
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Several lines of evidence suggest a link between age-related macular degeneration and retinal cholesterol maintenance. Cytochrome P450 27A1 (CYP27A1) is a ubiquitously expressed mitochondrial sterol 27-hydroxylase that plays an important role in the metabolism of cholesterol and cholesterol-related compounds. We conducted a comprehensive ophthalmic evaluation of mice lacking CYP27A1. We found that the loss of CYP27A1 led to dysregulation of retinal cholesterol homeostasis, including unexpected upregulation of retinal cholesterol biosynthesis. Cyp27a1(-/-) mice developed retinal lesions characterized by cholesterol deposition beneath the retinal pigment epithelium. Further, Cyp27a1-null mice showed pathological neovascularization, which likely arose from both the retina and the choroid, that led to the formation of retinal-choroidal anastomosis. Blood flow alterations and blood vessel leakage were noted in the areas of pathology. The Cyp27a1(-/-) retina was hypoxic and had activated Muller cells. We suggest a mechanism whereby abolished sterol 27-hydroxylase activity leads to vascular changes and identify Cyp27a1(-/-) mice as a model for one of the variants of type 3 retinal neovascularization occurring in some patients with age-related macular degeneration.
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