Abstract 048: The Sphingosine-1-phosphate Receptor S1P1 Regulates Kidney Vascular Development and Heart Development

Sphingosine 1-phosphate receptor 1 (S1P1) is one of the five G-protein coupled receptors activated by Sphingosine 1-phosphate, which is a bioactive sphingolipid metabolite crucial in many biological processes, including vascular development. It has been reported that deletion of S1P1 in mice results in embryonic lethality at E12.5-14.5 due to failure of migration and/or differentiation of vascular smooth muscle cells (vSMCs) and pericytes and that S1P1 functions autonomously in endothelial cells (ECs) as an inhibitor of angiogenesis. However, due to the early lethality of the aforementioned S1P1-/- mice, the role of S1P1 in kidney vascular development has not been determined. This study was designed to test the hypothesis that the S1P1 is crucial for the differentiation, assembly and maturation of the renal vasculature. Using EC-SCL-CreERT mice that specifically express tamoxifen inducible Cre in EC progenitors crossed with S1P1fl/fl and Rosa-LacZ reporter mice, we generated mice with timed deletion of S1P1 in ECs during kidney development (EC-S1P1KO). The knockout embryos with tamoxifen treatment develop severe edema, hemorrhages (36%, 8/22) or die (50%, 11/22) at E14.5 to E16.5, which may be caused by heart failure. Using histological methods including X-gal staining and immunohistochemistry for markers of ECs and mural cells, we found that the EC-S1P1KO embryos develop abnormal glomerular capillaries, dilated renal arteries and veins, disrupted vSMC coating of renal arteries and arterioles and absence of lymphatic endothelium. Further, thinner inter-ventricular septum, thinner ventricular myocardial compact layer and dilated myocardial capillaries are found in EC-S1P1KO embryos. Cross-transplantation studies of E12.5 kidneys from EC-S1P1KO and control mice under the kidney capsule of WT adult mice revealed that the kidney vascular abnormalities are intrinsic, due to the lack of S1P1 in renal EC precursors, and not secondary to the extra-renal anomalies. These studies suggest that endothelial S1P1 is an essential regulator of both kidney vascular development and heart development.