title: Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis.
abstract: 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 Müller 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.
authors: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
authors: Saida
authors: S
authors: Omarova
authors: Casey D
authors: CD
authors: Charvet
authors: Rachel E
authors: RE
authors: Reem
authors: Natalia
authors: N
authors: Mast
authors: Wenchao
authors: W
authors: Zheng
authors: Suber
authors: S
authors: Huang
authors: Neal S
authors: NS
authors: Peachey
authors: Irina A
authors: IA
authors: Pikuleva
mesh_terms: D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002829:Choroid / Q000098:blood supply; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis; D006801:Humans; D008268:Macular Degeneration / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000002:abnormalities*
chemical_list: D002784:Cholesterol; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse