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Diabetes 54:785-794, 2005
© 2005 by the American Diabetes Association, Inc.
Impaired Retinal Angiogenesis in Diabetes
Role of Advanced Glycation End Products and Galectin-3
1 Ophthalmology and Vision Science Research Centre, Queens University of Belfast, Belfast, Northern Ireland, U.K
2 Metabolic Unit, Royal Victoria Hospital, Belfast, Belfast, Northern Ireland, U.K
3 Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, California
4 Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina
Suppression of angiogenesis during diabetes is a recognized phenomenon but is less appreciated within the context of diabetic retinopathy. The current study has investigated regulation of retinal angiogenesis by diabetic serum and determined if advanced glycation end products (AGEs) could modulate this response, possibly via AGE-receptor interactions. A novel in vitro model of retinal angiogenesis was developed and the ability of diabetic sera to regulate this process was quantified. AGE-modified serum albumin was prepared according to a range of protocols, and these were also analyzed along with neutralization of the AGE receptors galectin-3 and RAGE. Retinal ischemia and neovascularization were also studied in a murine model of oxygen-induced proliferative retinopathy (OIR) in wild-type and galectin-3 knockout mice (gal3–/–) after perfusion of preformed AGEs. Serum from nondiabetic patients showed significantly more angiogenic potential than diabetic serum (P < 0.0001) and within the diabetic group, poor glycemic control resulted in more AGEs but less angiogenic potential than tight control (P < 0.01). AGE-modified albumin caused a dose-dependent inhibition of angiogenesis (P < 0.001), and AGE receptor neutralization significantly reversed the AGE-mediated suppression of angiogenesis (P < 0.01). AGE-treated wild-type mice showed a significant increase in inner retinal ischemia and a reduction in neovascularization compared with non-AGE controls (P < 0.001). However, ablation of galectin-3 abolished the AGE-mediated increase in retinal ischemia and restored the neovascular response to that seen in controls. The data suggest a significant suppression of angiogenesis by the retinal microvasculature during diabetes and implicate AGEs and AGE-receptor interactions in its causation.
Address correspondence and reprint requests to Professor A.W. Stitt, Ophthalmic Research Centre, Queen’s University Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland. E-mail: a.stitt{at}qub.ac.uk
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