Pathophysiological roles of the sphingosine-1-phosphate signaling system in vivo

点击翻译按钮获取中文摘要

Sphingosine-1-phosphate (S1P) is a plasma lipid mediator that is produced by sphingosine kinase 1 (SphK1) in erythrocytes to mediate diverse biological activities via 5 members of the G protein-coupled S1P receptor subtypes. We previously cloned S1PR2 as an orphan G protein-coupled receptor and identified S1P as the physiological ligand. In fact S1PR2 turned out to be the first G protein-coupled receptor that negatively regulates cell migration. In the present study we generated SphK1 transgenic mice and S1PR2 knockout mice to investigate in vivo roles for the S1P signaling system. We found that SphK1 transgenic mice show resistance against acute myocardial ischemia whereas they develop spontaneous cardiac remodeling and fibrosis through mechanisms involving S1PR3 and transactivation of TGFβ signaling pathway and reactive oxygen-dependent processes. We also found that deletion of S1PR2 resulted in enhancement of tumor angiogenesis and tumor growth. Studies in cultured lung endothelial cells and bone marrow transplantation experiments indicated that S1PR2 expressed on vascular endothelial cells and bone marrow-derived myeloid cells in concert inhibit tumor angiogenesis, resulting in suppression of tumor progression, providing molecular basis for anti-angiogenic cancer therapy with S1PR2-selective agonist.