Stabilization of HIF-1α in Human Retinal Endothelial Cells Modulates Expression of miRNAs and Proangiogenic Growth Factors.

Francesca Lazzara,Filippo Drago,Claudio Bucolo,Francesco Petrillo,Settimio Rossi,Carlo Gesualdo,Chiara Bianca Maria Platania,Michele D’Amico,Maria Consiglia Trotta,Marilena Galdiero

doi:10.3389/fphar.2020.01063

Abstract

Retinal hypoxia is one of the causative factors of diabetic retinopathy and is also one of the triggers of VEGF release. We hypothesized that specific dysregulated miRNAs in diabetic retinopathy could be linked to hypoxia-induced damage in human retinal endothelial cells (HRECs). We investigated in HRECs the effects of chemical (CoCl2) hypoxia on the expression of HIF-1α, VEGF, PlGF, and of a focused set of miRNAs. We found that miR-20a-5p, miR-20b-5p, miR-27a-3p, miR-27b-3p, miR-206-3p, miR-381-3p correlated also with expression of TGFβ signaling pathway genes in HRECs, challenged with chemical hypoxic stimuli. In conclusion, our data suggest that retinal angiogenesis would be promoted, at least under HIF-1α activation, by upregulation of PlGF and other factors such as miRNAs, VEGFA, and TGFβ1.

Highlights

Diabetic retinopathy (DR), a complication of diabetes, is a microvascular disease with a strong inflammatory imprinting
hypoxiainducible factor-1 a (HIF-1a) is a well-known inducer of vascular endothelial growth factor (VEGFA) and placental growth factor (PlGF) (Aiello et al, 1994; Ozaki et al, 1999; Arjamaa and Nikinmaa, 2006; Abu El-Asrar et al, 2012; Zimna and Kurpisz, 2015; Charnock-Jones, 2016; Rodrigues et al, 2016; Mitsui et al, 2018), but the HIF-1a protein levels did not correlate with expression pattern of VEGFA, within the analyzed time-points (Figure 1B)
Because retinal hypoxia is detrimental in DR, exacerbating retinal damage and angiogenesis (Aiello et al, 1994; Arjamaa and Nikinmaa, 2006; Abu El-Asrar et al, 2012), we aimed at testing the hypothesis that these miRNAs would be modulated in human retinal endothelial cells, treated with CoCl2 in order to stabilize HIF-1a

Summary

Introduction

Diabetic retinopathy (DR), a complication of diabetes, is a microvascular disease with a strong inflammatory imprinting. Vascular endothelial growth factor (VEGF) is a key player in retinal neovascularization, and intraocular injections of anti-VEGF agents are currently the established therapies for diabetic macular edema, along with steroids (Bandello et al, 2012). During DR progression, local or global changes in retinal oxygenation may cause the development of hypoxic areas (Arden and Sivaprasad, 2012) and oxidative stress (Bucolo et al, 2006). Similar to the etiopathogenesis of retinopathy of prematurity (ROP), induction of hypoxiainducible factor-1 a (HIF-1a) may be responsible for the production of vascular endothelial growth factor (VEGFA), which is the main cause of retinal neovascularization (Aiello et al, 1994; Arjamaa and Nikinmaa, 2006; Abu El-Asrar et al, 2012).

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Conclusion