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A.W. Stitt, C. McGoldrick, D.M. McDonald, D. McCance, T.A. Gardiner; Suppression of Angiogenesis by Serum From Patients With Pre-Proliferative Diabetic Retinopathy and its Modulation by Advanced Glycation Endproducts (AGEs) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3296.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: As a vasodegenerative disease, diabetic retinopathy (DR) also shows many features of impaired vascular repair until the very late stages when retinal ischaemia drives a neovascular response. We have investigated the angiogenic potential of retinal microvascular endothelial cells grown in serum from diabetic patients at either the vasogenerative or vasoproliferative stage of DR. We also examined a modulatory role for serum-derived proteins that had been modified by advanced glycation. Methods: Using retinal microvascular endothelial cells, a novel 3-D in vitro model of angiogenesis was developed which incorporates key phenomena of cell proliferation, migration, tube formation and invasion. Invasion of pre-formed retinal vascular tubes into a secondary matrix was quantified after exposure to non-diabetic serum or serum from diabetic patients (n=6/group). Using this system the angiogenic potential of serum from patients classified as well-controlled (WC), as assessed by HbA1c, was compared with that from a poorly-controlled (PC) group. Also, serum from patients with proliferative retinopathy was compared to that of a group with non-proliferative retinopathy. AGE-modified serum albumin was also analysed in this model system along with neutralisation of AGE-receptors. Results: Serum from non-diabetic patients showed significantly greater angiogenic potential than diabetic serum (p<0.0001), while that from the WC diabetic group was significantly pro-angiogenic relative to the PC group. Serum from patients with proliferative DR showed greater stimulation of angiogenesis when compared to the background DR group (p<0.04) although this was still significantly less than non-diabetic controls. Co-incubation with VEGF neutralising antibodies significantly reduced angiogenesis elicited by serum from the proliferative DR group, in a dose-dependent manner (p<0.01). AGE-modified albumin caused inhibition of angiogenesis (p<0.001) when compared to native albumin controls and AGE-receptor neutralisation significantly reversed the AGE-mediated suppression of angiogenesis (p<0.01). Conclusions: There is significant suppression of retinal angiogenesis during diabetes. DR may have a significant anti-angiogenic aetiology, an effect mediated, at least in part, by serum-derived AGEs. This may have implications for microvascular repair during the vaso-degenerative stages of DR.
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