Purpose: Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule with significant pathophysiological importance, but its role in retinal neovascular diseases is unknown. Hydrogen sulfide is generated from L-cysteine by cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and/or 3-mercaptopyruvate sulfurtransferase (3-MST). The aim of this study was to investigate the role of H2S in retinal neovascularization (NV) in ischemia-induced retinopathy.
Methods: Studies were performed in a murine model of oxygen-induced retinopathy (OIR). Hydrogen sulfide was detected with a fluorescent assay. Western blots and immunohistochemistry were used to assess the changes of H2S-producing enzymes. Gene deletion and pharmacologic inhibition were used to investigate the role of H2S in retinal NV.
Results: Hydrogen sulfide production was markedly increased in retinas from OIR mice compared with those from room air (RA) controls. Cystathionine-β-synthase and CSE were significantly increased in OIR retinas, whereas 3-MST was not changed. Cystathionine-β-synthase was expressed throughout the neuronal retina and upregulated in neurons and glia during OIR. Cystathionine-γ-lyase was also localized to multiple retinal layers. Its immunoreactivity was prominently increased in neovascular tufts in OIR. Pharmacologic inhibition of CBS/CSE or genetic deletion of CSE significantly reduced retinal NV in OIR.
Conclusions: Our data indicate that the H2S-generating enzymes/H2S contributes to retinal NV in ischemia-induced retinopathy and suggest that blocking this pathway may provide novel therapeutic approaches for the treatment of proliferative retinopathy.