Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis
Saida Omarova, … , Neal S. Peachey, Irina A. Pikuleva
Saida Omarova, … , Neal S. Peachey, Irina A. Pikuleva
Published July 23, 2012
Citation Information: J Clin Invest. 2012;122(8):3012-3023. https://doi.org/10.1172/JCI63816.
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Research Article Ophthalmology

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

Saida Omarova, Casey D. Charvet, Rachel E. Reem, Natalia Mast, Wenchao Zheng, Suber Huang, Neal S. Peachey, Irina A. Pikuleva

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Figure 4

Focal intraretinal NV and Müller cell activation in Cyp27a1–/– mice.

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Focal intraretinal NV and Müller cell activation in Cyp27a1–/– mice. P...
Panels are representative of stainings carried out on adjacent retinal sections in Cyp27a1–/– mice (A–H) or through corresponding regions in Cyp27a1+/+ mice (I–M). (A and I) H&E staining. (C, F, and K) Stainings with a marker for blood vessels, tomato lectin (in red), which is a less specific blood-vessel marker than isolectin B4, binding to photoreceptors. (D, G, and L) Localization of GFAP, a marker of activated Müller cells (in yellow). (E, H, and M) Localization of GS expressed constitutively in Müller cells (in green). (B and J) Negative control sections treated with serum from nonimmunized animal. For fluorescent images, nuclei were stained with DAPI (in blue), and immunoreactivity/lectin binding was detected by DyLight 649–conjugated (in yellow), DyLight 549–conjugated (in red), and DyLight 488–conjugated (in green) fluorophores. Light blue arrows (C) indicate retinal blood vessels in different retinal layers; white arrow (D) indicates increased GFAP staining in the OPL and ONL in the area of pathology; gold arrows (E and H) indicate disorganized Müller cell bodies in Cyp27a1–/– specimen; and pink arrows (M) indicate proper organization of Müller cell bodies in Cyp27a1+/+ specimen. Scale bars: 30 μm. Original magnification, ×400.