Endothelial Lipase Is a Critical Determinant of High-Density Lipoprotein–Stimulated Sphingosine 1-Phosphate–Dependent Signaling in Vascular Endothelium

Objective—In addition to an extensively characterized role of high-density lipoprotein (HDL) in reverse cholesterol transport, bioactive lipids bound to HDL can also exert diverse vascular effects. Despite this, integration of HDL action in the vasculature with pathways that metabolize HDL and release bioactive lipids has been much less explored. The effects of HDL on endothelial cells are mediated in part by HDL-associated sphingosine 1-phosphate (S1P), which binds to S1P1 receptors and promotes activation of endothelial NO synthase (eNOS) and the kinase Akt. In these studies, we characterized the role of endothelial lipase (EL) in the control of endothelial signaling and biology, including those mediated by HDL-associated S1P. Approach and Results—HDL-induced angiogenesis in aortic rings from EL-deficient (EL−/−) mice was markedly decreased compared with wild-type controls. In cultured endothelial cells, small interfering RNA–mediated knockdown of EL abrogated HDL-promoted endothelial cell migration and...