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Ultrastructural Changes in a Murine Model of Graded Bruch Membrane Lipoidal Degeneration and Corresponding VEGF₁₆₄ Detection

¹From the Department of Ophthalmology, Medical University of Vienna, Vienna, Austria; ²Department of Ophthalmology, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany; ³Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL; ⁴Department of Ophthalmology, University of Erlangen, Erlangen, Germany; and ⁵Arteriosclerosis Research Group, Department of Internal Medicine, University of Schleswig-Holstein, Luebeck, Germany.

PURPOSE. To evaluate ultrastructural changes in low-density lipoprotein (LDL) receptor knockout (R^–/–) mice consuming different diets as a potential model of Bruch membrane (BM) lipoidal degeneration and to determine the distribution and concentration of VEGF₁₆₄ in this mouse model.

METHODS. Eight-month-old LDL-R^–/– mice and wild-type controls were fed a standard or a high-fat diet. Animals were killed, and plasma cholesterol levels were determined. Using transmission electron microscopy, BM thickness, lipid vacuole size, and retinal pigment epithelial height were measured. Degenerative alterations of choriocapillaris, RPE, and photoreceptors were described and graded. Using light microscopy, VEGF₁₆₄ immunohistoreactivity was graded. Neutral lipids were detected with oil red O.

RESULTS. Choriocapillaris, BM, RPE, and photoreceptors of standard diet control animals showed a regular architecture. LDL-R^–/– mice fed a standard diet showed more diffuse focal alterations than control mice fed a high-fat diet. Within the choriocapillaris, the basement membrane was thickened, endothelial fenestration numbers were reduced, and lumina narrowed. BM thickness increased with a loss of regular structure. With pronounced BM degeneration, lipid inclusions increased in number and size. A decrease in retinal pigment epithelial cell height was accompanied by signs of intracellular degeneration. Photoreceptor outer segments showed focal degeneration and the formation of vacuoles. All these changes were most pronounced in LDL-R^–/– mice after a high-fat diet. VEGF₁₆₄ was found exclusively in the choriocapillaris, positively correlating with the amount of lipid accumulation in BM.

CONCLUSIONS. Feeding a standard or a high-fat diet to LDL-R^–/– mice and wild-type controls resulted in a reproducible model of graded BM lipoidal degeneration that resembled alterations in aged human eyes. This model provides a valuable tool for investigating biological responses to lipoidal degeneration.