Constant
or intense light degenerates the retina and retinal pigment
epithelial cells. Light generates reactive oxygen species and nitric
oxide leading to initial reactions of retinal degeneration. Apoptosis
is the primary mechanism of abnormal death of photoreceptors, retinal
ganglion cells, or retinal pigment epithelium (RPE) in degenerative
retinal diseases, including diabetic retinopathy and age-related macular
degeneration. The current study evaluated the function of erythropoietin
(EPO) on angiogenesis and apoptosis in the retina and RPE under oxidative
stress. We determined the pro-angiogenic and antiapoptotic mechanism
of EPO under stress conditions using a conditional EPO knockdown model
using siRNA, EPO addition, proteomics, immunocytochemistry, and bioinformatic
analysis. Our studies verified that EPO protected retinal cells from
light-, hypoxia-, hyperoxia-, and hydrogen peroxide-induced apoptosis
through caspase inhibition, whereas up-regulated angiogenic reactions
through vascular endothelial growth factor (VEGF) and angiotensin
pathway. We demonstrated that the EPO expression in the retina and
subsequent serine/threonine/tyrosine kinase phosphorylations might
be linked to oxidative stress response tightly to determining angiogenesis
and apoptosis. Neuroprotective roles of EPO may involve the balance
between antiapoptotic and pro-angiogenic signaling molecules, including
BCL-xL, c-FOS, caspase-3, nitric oxide, angiotensin, and VEGF receptor.
Our data indicate a new therapeutic application of EPO toward retinal
degeneration based on the dual roles in apoptosis and angiogenesis
at the molecular level under oxidative stress.