Increased expression of enzymes for sphingosine 1-phosphate turnover and signaling in human decidua during late pregnancy.

An appropriate balance between uterine quiescence and activation during pregnancy is essential for a successful outcome. Sphingosine 1-phosphate (S1P), a bioactive lipid, increases cell survival, proliferation, and angiogenesis, all important to maintain the pregnancy. Indeed progesterone increases sphingosine kinase 1 (SPHK1) mRNA, which produces S1P. In contrast, induction of prostaglandin endoperoxide synthase 2 by S1P and stimulation of SPHK1 by estradiol and cytokines suggests a role for S1P in the termination of pregnancy. Human decidua is important for regulating the maintenance and termination of pregnancy with production of progesterone receptors, cytokines, and prostaglandins. We hypothesized that S1P is produced by and acts on the decidua to stimulate production of mediators that induce labor. Our objective was to investigate the metabolism of S1P and its receptors in human decidua during pregnancy. We found that SPHK1 protein and activity positively correlated with increasing gestational age in human decidua parietalis. This was accompanied at term by increased expression of the S1P lyase, which irreversibly degrades S1P. This implies increased S1P turnover in the decidua at term. Although the mRNA level of phosphatidic acid phosphatase type 2A and 2B (PPAP2A,B), which dephosphorylate extracellular S1P, were increased at term, PPAP2 activity did not change. Sphingosine 1-phosphate receptor 3 protein expression also increased at term, indicating increased signaling by S1P in the decidua. There were no differences in any parameter tested in decidua from women in labor compared to those who were not. This work provides the first evidence of increased S1P synthesis, degradation, and signaling in human decidua during gestation.