In the retina, hypoxia is a key factor to trigger angiogenesis and to cause retinal cell death. The beta-adrenergic system interferes with angiogenesis-dependent diseases by regulating VEGF, but its role on retinal degeneration is unknown. Aim of the present study was to investigate the role of beta3-adrenergic receptors (BAR3) in retinal degenerative responses to the hypoxic insult. In mouse retinal explants, BAR3 were blocked pharmacologically or silenced with siRNAs. VEGFR2 was blocked with SU1498, iNOs and eNOS with AG, L-NIO or L-NAME. Quantitative RT-PCR, Western blot, colorimetric assays, immunohistochemistry and TUNEL were used. We found that BAR3 is localized to retinal blood vessels in which it is up-regulated by hypoxia and acts through iNOS/NO to control endogenous VEGF and angiogenic responses to hypoxia. We also found that BAR3 blockade enhances retinal degeneration in response to hypoxia by increasing apoptotic signals and retinal cell death thus suggesting neuroprotective action of BAR3. Pharmacological interaction with VEGF signalling demonstrates that BAR3 protects retinal cells through VEGF suggesting its important neuroprotective action in the retina. This conclusion may have implications for VEGF blockade within the context of ocular vascular diseases and suggests that modulation of BAR3 activity during ischemia may be a powerful means to achieve neuroprotection.

Grant of The Meyer Foundation to PB and The International Retinal Research Foundation to MDM.