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Juan Amaral, Ignacio R. Rodriguez; 7-ketocholesterol Induced Ocular Angiogenesis: A Potential Age-related Risk Factor in the Pathogenesis of Age-related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2011;52(14):2303.
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7-Ketocholesterol (7KCh), a toxic oxysterol found in atheromatous plaques is known to induce various inflammatory pathways. 7KCh has been implicated in the development of atherosclerosis, Alzheimer’s disease and cancer. In the aging eye, lipoprotein deposits are found in Bruch’s membrane and drusen. 7KCh is found associated with lipoprotein deposits in the pigment epithelium (RPE) and choriocapillaris of monkey retinas. Since inflammation and angiogenesis have been associated with AMD, this study evaluates the potential of 7KCh to induce ocular angiogenesis.
Wafers were prepared by crosslinking 7KCh complexed in hydroxypropyl-β-cyclodextrin (HPBCD) to polyethylene glycol and hyaluronic acid. The powder was made into 40 mg, 18 mm diameter wafers using a 15 ton hydraulic press. Using a 1 mm trephine, smaller wafers were punched. Wafers containing three different concentrations of 7KCh (3.6%, 7%, and 14%) were implanted in rat corneal pockets. Wafers containing LDL and oxidized LDL (oxLDL) were similarly prepared. After implantation, corneal vessel growth was evaluated for up to 14 days using sodium fluorescein injections and fluorescent microscopy to image corneal neovessels.
New vessels were observed to grow from the limbus by 3 days post-implantation. By 10 days, neovessels achieved maximum growth. All concentrations of 7KCh developed neovessels, no vessels were observed with control wafers (no 7KCh). The 7% 7KCh-containing wafers formed the largest viable vessels. The 3.6% wafers formed smaller vessels and the 14% formed "ghosts" vessels perhaps dues to increased cytotoxicity. Similarly, oxLDL wafers also developed well-formed corneal neovessels, while LDL controls were devoid of them.
Our data demonstrates that 7KCh is able to induce neovessel growth, supporting the hypothesis that the accumulation of oxidized lipoprotein deposits in the RPE/Bruch’s membrane/choriocapillaris complex may be implicated in the development of exudative AMD. This study is the first to demonstrate 7KCh-mediated angiogenesis in vivo.
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