Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization

Sphingosine‐1‐phosphate (S1P), the circulating HDL‐bound lipid mediator that acts via S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is unclear. Here, we show in a mouse model of oxygen‐induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom (−/−) mice which lack HDL‐bound S1P while they are suppressed in Apom ( TG ) mice which have more circulating HDL‐S1P. These results suggest that circulating HDL‐S1P activation of endothelial S1PR1 suppresses neovascular pathology in OIR. Additionally, systemic administration of ApoM‐Fc‐bound S1P or a small‐molecule Gi‐biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL‐S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetic patients and aging people.