Open AccessPotential role of the methylation of VEGF gene promoter in response to hypoxia in oxygen‐induced retinopathy: beneficial effect of the absence of AQP4
Author(s) -
Pisani Francesco,
Cammalleri Maurizio,
Dal Monte Massimo,
Locri Filippo,
Mola Maria Grazia,
Nicchia Grazia Paola,
Frigeri Antonio,
Bagnoli Paola,
Svelto Maria
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13348
Subject(s) - vascular endothelial growth factor , downregulation and upregulation , hypoxia (environmental) , retinal , transactivation , hypoxia inducible factors , angiogenesis , retina , biology , vascular endothelial growth factor a , microbiology and biotechnology , chemistry , endocrinology , cancer research , gene expression , gene , biochemistry , oxygen , vegf receptors , organic chemistry , neuroscience
Hypoxia‐dependent accumulation of vascular endothelial growth factor (VEGF) plays a major role in retinal diseases characterized by neovessel formation. In this study, we investigated whether the glial water channel Aquaporin‐4 (AQP4) is involved in the hypoxia‐dependent VEGF upregulation in the retina of a mouse model of oxygen‐induced retinopathy (OIR). The expression levels of VEGF, the hypoxia‐inducible factor‐1α (HIF‐1α) and the inducible form of nitric oxide synthase (iNOS), the production of nitric oxide (NO), the methylation status of the HIF‐1 binding site (HBS) in the VEGF gene promoter, the binding of HIF‐1α to the HBS, the retinal vascularization and function have been determined in the retina of wild‐type (WT) and AQP4 knock out (KO) mice under hypoxic (OIR) or normoxic conditions. In response to 5 days of hypoxia, WT mice were characterized by ( i ) AQP4 upregulation, ( ii ) increased levels of VEGF, HIF‐1α, iNOS and NO, ( iii ) pathological angiogenesis as determined by engorged retinal tufts and ( iv ) dysfunctional electroretinogram (ERG). AQP4 deletion prevents VEGF, iNOS and NO upregulation in response to hypoxia thus leading to reduced retinal damage although in the presence of high levels of HIF‐1α. In AQP4 KO mice, HBS demethylation in response to the beginning of hypoxia is lower than in WT mice reducing the binding of HIF‐1α to the VEGF gene promoter. We conclude that in the absence of AQP4, an impaired HBS demethylation prevents HIF‐1 binding to the VEGF gene promoter and the relative VEGF transactivation, reducing the VEGF‐induced retinal damage in response to hypoxia.