Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3.
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.
Stitt
Alan W
AW
Ophthalmic and Vision Science Research Centre, Queens University Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland. a.stitt@qub.ac.uk
McGoldrick
Ciara
C
Rice-McCaldin
Aine
A
McCance
David R
DR
Glenn
Josephine V
JV
Hsu
Daniel K
DK
Liu
Fu-Tong
FT
Thorpe
Suzanne R
SR
Gardiner
Tom A
TA
D000328:Adult; D000418:Albumins; D000818:Animals; D003920:Diabetes Mellitus / Q000097:blood* / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology; D037502:Galectin 3 / Q000097:blood / Q000235:genetics / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000097:blood / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology; D012171:Retinal Vessels / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D000418:Albumins; D037502:Galectin 3; D017127:Glycation End Products, Advanced; D007074:Immunoglobulin G; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D042461:Vascular Endothelial Growth Factor A