RRC ID 49599
Author Jiang H, Wu M, Liu Y, Song L, Li S, Wang X, Zhang YF, Fang J, Wu S.
Title Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells.
Journal J Neurochem
Abstract 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 (Srrnull ) 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 Srrnull mice contained less inducible nitric oxide synthase and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation-primed WT RPEs expressed more inducible NOS, produced more. NO and VEGF than did inflammation-primed Srrnull RPEs. When co-cultured with inflammation-primed Srrnull 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.
Volume 143(3)
Pages 375-388
Published 2017-11-1
DOI 10.1111/jnc.14214
PMID 28892569
MeSH Animals Blindness / etiology Blindness / genetics Blindness / pathology* Cells, Cultured Choroidal Neovascularization / genetics* Choroidal Neovascularization / pathology Cytokines / metabolism Disease Models, Animal Gene Expression Regulation / genetics* Gene Expression Regulation / radiation effects Lasers / adverse effects Lipopolysaccharides / pharmacology Macrophages / physiology Macrophages / radiation effects Mice Mice, Inbred C57BL Mice, Transgenic Mutation / genetics Nitric Oxide / metabolism* RNA, Messenger / metabolism Racemases and Epimerases / deficiency* Racemases and Epimerases / genetics Retinal Pigment Epithelium / drug effects Retinal Pigment Epithelium / metabolism* Serine / metabolism Vascular Endothelial Growth Factor A / metabolism*
IF 4.066
Times Cited 6
Mice RBRCGD000099