Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.
Biol Reprod. 2010 Mar;82(3):628-35. doi: 10.1095/biolreprod.109.081497. Epub 2009 Dec 9.
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.
妊娠期间子宫静止和激活之间的适当平衡对于成功妊娠至关重要。鞘氨醇 1-磷酸（S1P）是一种生物活性脂质，可增加细胞存活、增殖和血管生成，这些对于维持妊娠都很重要。事实上，孕激素会增加产生 S1P 的鞘氨醇激酶 1（SPHK1）mRNA。相比之下，S1P 诱导前列腺素内过氧化物合酶 2 的诱导以及雌二醇和细胞因子刺激 SPHK1，表明 S1P 在妊娠终止中发挥作用。人蜕膜对于调节妊娠的维持和终止具有重要作用，其产生孕激素受体、细胞因子和前列腺素。我们假设 S1P 由蜕膜产生并作用于蜕膜，以刺激诱导分娩的介质的产生。我们的目的是研究 S1P 及其受体在妊娠期间人蜕膜中的代谢。我们发现 SPHK1 蛋白和活性与人蜕膜壁层的妊娠年龄呈正相关。这伴随着 S1P 裂合酶表达的增加，S1P 裂合酶不可逆地降解 S1P。这意味着在足月时蜕膜中 S1P 周转率增加。尽管磷酸酶 2A 和 2B（PPAP2A，B）的 mRNA 水平增加，PPAP2A，B 可使细胞外 S1P 去磷酸化，但 PPAP2 活性并未改变。S1P 受体 3 蛋白表达也在足月时增加，表明 S1P 在蜕膜中的信号转导增加。与未分娩的女性相比，分娩女性的蜕膜中任何参数均无差异。这项工作首次提供了证据，表明在妊娠期间人蜕膜中 S1P 的合成、降解和信号转导增加。
