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Neuroprotective factors against retinal injury in response to hypoxia: new perspectives
Author(s) -
BAGNOLI P,
DAL MONTE M
Publication year - 2012
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.1755-3768.2012.3232.x
Subject(s) - neuroprotection , enos , retinal , retina , angiogenesis , hypoxia (environmental) , neovascularization , pharmacology , tunel assay , apoptosis , vascular endothelial growth factor a , vascular endothelial growth factor , biology , microbiology and biotechnology , chemistry , neuroscience , endocrinology , cancer research , nitric oxide synthase , nitric oxide , biochemistry , vegf receptors , organic chemistry , oxygen
Purpose In the retina, hypoxia is considered one of the key factors to trigger angiogenesis and to promote apoptosis by reducing photoreceptors and other retinal neurons, each of them contributing to vision loss. We recently demonstrated that the beta‐adrenergic system interferes with angiogenesis‐dependent diseases in the retina by regulating endogenous VEGF. Aim of the present study was to investigate the role of distinct beta‐adrenergic receptors (BARs)in neurodegenerative processes in response to hypoxia. Methods Ex vivo mouse retinal explants and in vivo models were used. BARs were blocked with antagonists or silenced with siRNAs. VEGFR2 was blocked with SU1498, whereas iNOs and eNOS with AG, L‐NIO or L‐NAME. mRNA levels were evaluated with quantitative RT‐PCR. BARs, iNOS, eNOS and apoptotic signals were determined with Western blot. Immunohistochemistry was used to localize BARs and to assess neovascularization. VEGF release and NO production were measured with colorimetric assays. Hoechst and TUNEL were used to evaluate cell loss. Results Among the BARs, BAR3 is localized to blood vessels, is upregulated by hypoxia and acts through iNOS/NO to control VEGF levels and degenerative responses to the hypoxic insult. In particular, BAR3 blockade is accompanied by increased levels of apoptotic signals and cell loss. Pharmacological interaction with the VEGF signalling demonstrates that BAR3 exerts a protective action on retinal cells through a modulation of endogenous VEGF. Conclusion Our findings demonstrate that modulation of BAR3 activity during ischemia may be a powerful means to achieve neuroprotection. VEGF's role in retinal cell survival has important implications for treatments with VEGF blockade within the context of ocular vascular diseases.