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The role of hypoxia‐inducible factors in age‐related macular degeneration
Author(s) -
André Helder
Publication year - 2019
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2019.5100
Subject(s) - macular degeneration , choroidal neovascularization , hypoxia (environmental) , retinal pigment epithelium , retinal , hypoxia inducible factors , downregulation and upregulation , medicine , vascular endothelial growth factor , in vivo , angiogenesis , neovascularization , cancer research , biology , ophthalmology , vegf receptors , chemistry , genetics , gene , organic chemistry , oxygen
Abstract Purpose Pathophysiological mechanisms of age‐related macular degeneration (AMD) have been attributed mainly to local tissue ischemia or the presence of low‐grade inflammatory reaction. A fundamental difference between both types of AMD is the increased vascular endothelial growth factor (VEGF) level in neovascular AMD (nAMD), a result of underlying tissue hypoxia and upregulation of hypoxia‐inducible factor (HIF) in the retinal pigment epithelium (RPE), leading to choroidal neovascularization (CNV). Here, we will present a summary of our studies in the benefits of mitigating HIF responses in models of nAMD. Methods We have addressed the hypoxia response in RPE cells in vitro (retinal cells cultures) and in vivo (laser‐induced CNV model), using tissue ischemia molecular modulators (UPARANT), HIF‐specific inhibitors (Echinomycin) and HIF molecular negative regulators (prolyl hydroxylase domain 2) as a negative‐modulators of HIF. Results We have demonstrated that expression of HIF is upregulated in RPE cells in vivo during progression of CNV, and was associated with increased VEGF levels. Collectively, our data has demonstrated a role for HIF in nAMD, and that negative‐regulation of the hypoxia pathway in RPE cells abnegates the increase in VEGF, together with other HIF‐mediated factors, significantly reducing CNV associated with nAMD. Conclusions Due to the protracted nature of AMD, the multifactorial mechanisms involved, and current therapeutic limitations there is a great need for long‐term therapies that can mitigate multiple angiogenic and inflammatory factors known to be associated with nAMD, allowing for sustainable treatments. We have established a molecular role for HIFs in nAMD progression, and have identified molecules capable of regulating hypoxia processes that have pronounced translational therapeutic potential. Reference H André et. al. IOVS 2015; M Cammalleri et al. IOVS 2016; A Takei et al. Sci Rep 2017; F. Plastino et al. EVER2019 abstract.