Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

Choroidal neovascularization ( CNV ) is a leading cause of blindness in age‐related macular degeneration. Production of vascular endothelial growth factor ( VEGF ) and macrophage recruitment by retinal pigment epithelial cells ( RPE ) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase ( SR ) is expressed in retinal neurons and glial cells, and its product, d ‐serine, is an endogenous co‐agonist of N ‐methyl‐ d ‐aspartate receptor. Activation of the receptor results in production of nitric oxide ( . NO ), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV . With laser‐injured CNV mice, we found that inactivation of SR ‐coding gene ( Srr null ) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo . RPE from wild‐type ( WT ) mice expressed SR . To explore the possible downstream target of SR inactivation, we showed that choroid/ RPE homogenates extracted from laser‐injured Srr null mice contained less inducible nitric oxide synthase and decreased phospho‐ VEGFR 2 compared to amounts in WT mice. In vitro , inflammation‐primed WT RPE s expressed more inducible NOS, produced more . NO and VEGF than did inflammation‐primed Srr null RPE s. When co‐cultured with inflammation‐primed Srr null RPE , significantly fewer RF /6A‐a cell line of choroidal endothelial cell, migrated to the opposite side of the insert membrane than did cells co‐cultured with pre‐treated WT RPE . Altogether, SR deficiency reduces RPE response to laser‐induced inflammatory stimuli, resulting in decreased production of a cascade of pro‐angiogenic cytokines, including . NO and VEGF , and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis.