ApoM-bound S1P acts via endothelial S1PR1 to suppress choroidal neovascularization and vascular leak

Neovascular age-related macular degeneration (nAMD) is a major cause of vision loss in the elderly. Vascular endothelial growth factor (VEGF) inhibitors, which are approved for the treatment of nAMD, require repetitive intraocular injections and suffer from partial and non-durable treatment response. We report here that circulating sphingosine 1-phosphate (S1P) carried by apolipoprotein M (ApoM) acts through the endothelial S1P receptor 1 (S1PR1) to suppress choroidal neovascularization (CNV) in laser-induced mouse nAMD model. Low plasma ApoM increased whereas high plasma ApoM reduced laser-induced CNV. In addition, endothelial S1pr1 knockout and overexpressing transgenic mice showed larger and reduced CNV lesion size, respectively. Systemic administration of ApoM-Fc, an engineered S1P chaperone protein, not only attenuated CNV to an equivalent degree as anti-VEGF antibody treatment but also suppressed vascular permeability. We suggest that the circulating ApoM-bound S1P action on endothelial S1PR1 provides a novel therapeutic strategy to treat nAMD.