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C. F. Bento, R. Fernandes, P. Pereira; Ang-2 and Vegf: Two Players in the Orchestration of Vascular Dysfunction in the Early Stages of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5381.
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Increased retinal levels of methylglyoxal (MGO) in animal models of diabetes have been implicated in the formation of acellular capillaries and pericytes dropout, suggesting an important role for MGO in the vascular dysfunction observed in the early stages of diabetic retinopathy (DR). It has been further shown that MGO increases the expression of angiopoietin-2 (Ang-2), which provides a key-destabilizing signal for vessels, leading to regression in the absence of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF). In this study, we hypothesize that increased levels of MGO in retinal pigment epithelium (RPE) cells imbalances the ratio between Ang-2 and VEGF, leading to endothelial cell death and vascular regression.
ARPE-19 cells were subjected to hypoxia in the presence of MGO, two main features of DR. The levels of VEGF and Ang-2 secreted into the culture medium were assessed by ELISA. Retinal endothelial cells were subsequently treated with the pre-conditioned media of the ARPE-19 cells, as well as with different ratios of VEGF and Ang-2 recombinant proteins. Apoptosis was determined by immunoblot against Bax and Bcl-2, while endothelial cell proliferation was assessed by BrdU-incorporation and fibrin gel angiogenic assays.
MGO increases the levels of Ang-2 and strongly decreases the levels of VEGF secreted by ARPE-19 cells in response to hypoxia. Data also show that VEGF downregulation is the result of increased HIF-1 degradation by the ubiquitin-proteasome pathway and decreased HIF-1 transcriptional activity. The VEGF/Ang-2 imbalance generated by MGO significantly increased the expression of BAX and decreased the levels of Bcl-2 on endothelial cells. Moreover, this imbalance also led to low proliferation rate of the endothelial cells, as assessed by low BrdU incorporation on DNA.
The VEGF/Ang-2 imbalance induced by accumulation of MGO activates the apoptotic cascade and induces low proliferation rate of retinal endothelial cells, possibly leading to vessel regression in situations of high availability of MGO, such as DR.
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