Signaling Pathways Involved in Sphingosine Kinase Activation and Sphingosine-1-Phosphate Release in Rat Myometrium in Late Pregnancy: Role in the Induction of Cyclooxygenase 2

Abstract

We investigated the regulation of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) axis and its role during pregnancy in the rat myometrium. SphK1 and SphK2 were coexpressed in myometrium during gestation. The levels and activity of SphK1/2 were modest at midgestation (d 12), increased at d 19 and progressively declined to low at postpartum. Similar patterns were observed for the phosphorylation of ERK and protein kinase C (PKC). Inhibition of PKC and ERK reduced SphK1/2 activity. In late pregnancy, levels of cyclooxygenase 2 (COX2) increased in parallel to SphK levels. Using a pharmacological approach, we demonstrated that in primary cultures of myometrial cells from d-19 pregnant rats, induction of COX2 was mediated by 4beta-phorbol 12,13-dibutyrate and IL-1beta through sequential activation of PKC, ERK1/2, and SphK1. S1P produced by SphK1 was released in the medium. Addition of S1P, IL-1beta or 4beta-phorbol 12,13-dibutyrate enhanced COX2 levels via Gi protein. Interestingly, S1P was also released by myometrial tissues at late gestation. This event was dependent on PKC/ERK/SphK1. By contrast, in d-12 myometrial tissues, the release of S1P was markedly reduced in association with low levels of SphK1 and COX2. However, prolonged incubation of myometrium from midgestation led to the induction of COX2. This effect was blocked by SphK inhibitors, providing evidence of the close relationship between SphK activity and COX2 induction in rat myometrium. Overall, our findings provided insight into the physiological relevance of the SphK activation and S1P release in uterine smooth muscle during gestation.

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

“…Myometrial ERK2 phosphorylation increased significantly with advancing GA in accordance with previously reported results in the pregnant rat uterus (Oldenhof et al 2002, Serrano-Sanchez et al 2008. We observed no change in ERK1/2 phosphorylation in the myometrium with labor, which agrees with a previous report on the rat myometrium (Oldenhof et al 2002) but differs from that of Li et al (2003) who reported increased ERK2 phosphorylation in the rat uterus during labor.…”

“…In pregnant rats, the abundance of activated ERK in myometrial cells increases with gestation (Oldenhof et al 2002, Serrano-Sanchez et al 2008 and labor onset (Li et al 2003). In animals induced to deliver preterm (PT) by administration of the progesterone receptor antagonist RU486, concurrent inhibition of ERK signaling delayed preterm labor and decreased myometrial contractility (Li et al 2004).…”

The Effect of Gestational Age on Angiogenic Gene Expression in the Rat Placenta

“…SGPL1, thus, regulates the available pool of S1P and inhibits its signalling activities. SGPL1 may regulate S1P-induced Ptgs2 expression in the rat myometrium [32]. In this study, Sgpl1 expression increased 2.6 fold during gestation from E14.25 to E20.…”

MAPK14 Cooperates with MAPK3/1 to Regulate Endothelin-1-Mediated Prostaglandin Synthase 2 Induction and Survival in Leiomyoma but Not in Normal Myometrial Cells1

“…Taking into account that the PTGS2/PGE2 axis plays an important role in myometrial physiology [29,50] and tumor growth [14], and that MAPK could regulate the expression of this enzyme [25][26][27], we investigated the potential role of ET-1 and subsequent MAPK3/1/MAPK14 activation in PTGS2 expression. Our data demonstrate that, in ELT3, exogenous PGE2 added in the medium induced an antiapoptotic effect.…”

“…We previously reported that, in ELT3 cells, the sphingosine-kinase 1/sphingosine 1 phosphate (S1P) pathway contributes to the ET-1-induced antiapoptotic effect [13]. Furthermore, S1P is involved in the up-regulation of PTGS2 in late pregnant rat myometrium [50] and in ELT3 cells (data not shown). Therefore, a potential relationship between PTGS2 and S1P axis may occur in ELT3 cells.…”