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Haley Megarity, Monika Deshpande, Savalan Babapoor-Farrokhran, Brooks Puchner, Gregg Semenza, Silvia Montaner, Akrit Sodhi; Hypoxia-Inducible Factor 1-Regulated Angiogenic Cytokines in Prolifeartive Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4050.
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Recent studies have demonstrated that monthly intravitreal injections with therapies targeting VEGF delays the development of PDR in some, but not all, treated patients. This suggests that additional factor(s) may contribute to the development of retinal neovascularization in diabetic patients. In addition to VEGF, hypoxia inducible factor (HIF)-1 regulates the expression of other angiogenic factors in ischemic retinal disease, and plays a central role in the promotion of retinal neovascularization in PDR. Here we set out to examine the potential contribution of three other HIF-1-regulated angiogenic cytokines, angiopoietin 2 (ANGPT2), erythropoietin (EPO), and angiopoietin-like 4 (ANGPTL4), all previously implicated in the promotion of diabetic eye disease, to the development of PDR.
HIF-1-regulation of VEGF, AGPT2, EPO, and ANGPTL4 mRNA and protein expression was assessed in vitro by qPCR and ELSIAs in primary and immortalized (MIO-M1) retinal Müller cells in vitro or the OIR model in vivo. The angiogenic potential was assessed using the tubule formation assay. Expression of these factors in vitreous biopsies from patients with active NV due to PDR was determined by ELISA. Complementary IHC studies were performed in a second group of eyes from PDR patients. Mann-Whitney U test and Spearman correlation statistical models were used to compare protein concentrations and to identify factors that independently correlate with PDR.
VEGF, ANGPT2, EPO and ANGPTL4 mRNA levels were elevated in hypoxic Müller cells in vitro and in the OIR model in vivo; inhibition of HIF-1 blocked their expression. However, protein levels of EPO and ANGPT2 were not significantly increased in retinal Müller cells, suggesting that these proteins may be expressed by a different cell type, or their local (intraocular) expression may be increased in diabetic eyes due to increased vascular permeability. Vitreous concentrations of VEGF, ANGPT2, EPO, and ANGPTL4 were all significantly higher in PDR patients compared to controls and correlated with the presence of PDR. Following anti-VEGF therapy, vitreous VEGF levels decreased; however levels of ANGPT2, EPO, and ANGPTL4 remained elevated.
In addition to VEGF, our results suggest that ANGPT2, EPO, and ANGPTL4 – or HIF-1 to target all four – may be potential therapeutic targets for the prevention and/or treatment of PDR.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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