This year we have identified novel functions for sphingolipids during pregnancy and the development of hearing:? ? Uterine decidualization, a process that occurs in response to embryo implantation, is critical for embryonic survival, and thus is a key event for successful pregnancy. Here we show that the sphingolipid metabolic pathway is highly activated in the deciduum during pregnancy, and disturbance of the pathway by disruption of sphingosine kinase genes causes severely defective decidualization, with severely compromised uterine angiogenesis, leading to maternally derived early pregnancy loss. Sphingosine kinase-deficient female mice, Sphk1-/- Sphk2+/-, exhibited both an enormous accumulation of dihydrosphingosine and sphingosine and a reduction in phosphatidylethanolamine levels in pregnant uteri. These mice also revealed increased cell death in decidual cells, decreased cell proliferation in undifferentiated stromal cells and severe breakage of decidual blood vessels, leading to uterine hemorrhage and early embryonic lethality. Thus, sphingolipid metabolism regulates proper uterine decidualization and angiogenesis. Our findings also suggest that disturbance in sphingolipid metabolism may be considered as a cause of pregnancy loss in humans.? ? The S1P2 receptor is a member of a family of G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. The receptor is widely expressed and linked to multiple G protein signaling pathways, but its physiological function has remained elusive. We have demonstrated that S1P2 receptor expression is essential for proper functioning of the auditory and vestibular systems. Auditory brainstem response analysis revealed that S1P2 receptor-null mice were deaf by one month of age. These null mice exhibited multiple inner ear pathologies. However, some of the earliest cellular lesions in the cochlea were found within the stria vascularis, a barrier epithelium containing the primary vasculature of the inner ear. Between 2 and 4 weeks after birth, the basal and marginal epithelial cell barriers and the capillary bed within the stria vascularis of the S1P2 receptor-null mice showed markedly disturbed structures. JTE013, an S1P2 receptor-specific antagonist, blocked the S1P-induced vasoconstriction of the spiral modiolar artery, which supplies blood directly to the stria vascularis and protects its capillary bed from high perfusion pressure. Vascular disturbance within the stria vascularis is a potential mechanism that leads to deafness in the S1P2 receptor-null mice.? ? Other findings from collaborative efforts:? ? S1P2 Receptor plays an essential role in pathologic angiogenesis of the retina and may be important in certain pathologies such as pediatric retinopathy of prematurity (ROP) condition and in diabetic retinopathy of the adult.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Bonder, Claudine S; Sun, Wai Y; Matthews, Tyson et al. (2009) Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation. Blood 113:2108-17
Hughes, Jeniter E; Srinivasan, Suseela; Lynch, Kevin R et al. (2008) Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages. Circ Res 102:950-8
Wu, Yun-Ping; Mizugishi, Kiyomi; Bektas, Meryem et al. (2008) Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Hum Mol Genet 17:2257-64
Kono, Mari; Allende, Maria Laura; Proia, Richard L (2008) Sphingosine-1-phosphate regulation of mammalian development. Biochim Biophys Acta 1781:435-41
Li, Xiaochun; Stankovic, Milena; Bonder, Claudine S et al. (2008) Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood 111:3489-97