Sphingosine-1-phosphate inhibition of placental trophoblast differentiation through a Gi-coupled receptor response

Johnstone, Edward D.; Chan, Gary; Sibley, Colin P.; Davidge, Sandra T.; Lowen, B.; Guilbert, Larry J.

doi:10.1194/jlr.m500095-jlr200

Cited by 40 publications

(42 citation statements)

References 40 publications

(62 reference statements)

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“…Perhaps uterine-derived sphingolipids attenuate trophoblast advancement into the uterus or regulate differentiation of the trophoblast lineage. Johnstone et al [40] recently demonstrated that S1P inhibited differentiation of primary human cytotrophoblasts into syncytiotrophoblasts through a G i -coupled receptor response, a pathway activated by S1P receptors. Sphingosine kinase 1 was also richly expressed in perivascular tissue surrounding larger maternal vascular canals.…”

Section: Discussionmentioning

confidence: 97%

Maternal and Embryonic Control of Uterine Sphingolipid-Metabolizing Enzymes During Murine Embryo Implantation1

Kaneko-Tarui

Zhang

Austin

et al. 2007

Biology of Reproduction

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During early gestation in invasively implanting species, the uterine stromal compartment undergoes dramatic remodeling, defined by the differentiation of stromal fibroblast cells into decidual cells. Lipid signaling molecules from a number of pathways are well-established functional components of this decidualization reaction. Because of a correlation in the events that transpire in the uterus during early implantation with known functions of bioactive sphingolipid metabolites established from studies in other organ systems, we hypothesized that uterine sphingolipid metabolism would change during implantation. By a combination of Northern blot, Western blot, and immunohistochemical analyses, we establish that enzymes at each of the major catalytic steps in the sphingolipid cascade become transcriptionally up-regulated in the uterus during decidualization. Each of the enzymes analyzed was up-regulated from Days of Pregnancy (DOP) 4.5-7.5. When comparing embryo-induced decidualization (decidual) with mechanically induced decidualization (deciduomal), sphingomyelin phosphodiesterase 1 (Smpd1) mRNA and sphingosine kinase 1 (SPHK1) protein were shown to be dually regulated in the endometrium by both maternal and embryonic factors. As measured by the diacyl glycerol kinase assay, ceramide levels rose in parallel with Smpd1 gene expression, suggesting that elevated transcription of sphingolipid enzymes results in heightened catalytic activity of the pathway. Altogether, these findings place sphingolipids on a growing list of lipid signaling molecules that become increasingly present at the maternal-embryonic interface.

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Section: Discussionmentioning

confidence: 97%

Maternal and Embryonic Control of Uterine Sphingolipid-Metabolizing Enzymes During Murine Embryo Implantation1

Kaneko-Tarui

Zhang

Austin

et al. 2007

Biology of Reproduction

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“…Recently, it has been reported that S1P inhibits cytotrophoblast differentiation and could be involved in the pathogenesis of preeclampsia in humans (47). Furthermore, S1P has been shown to induce a dose-dependent vasoconstriction in human uterine arteries during pregnancy (48).…”

Section: Figure 10mentioning

confidence: 99%

Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

Mizugishi

Li²,

Olivera³

et al. 2007

J. Clin. Invest.

135

116

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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 (Sphk) genes causes defective decidualization with severely compromised uterine blood vessels, leading to early pregnancy loss. Sphk-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 massive breakage of decidual blood vessels, leading to uterine hemorrhage and early embryonic lethality. Thus, sphingolipid metabolism regulates proper uterine decidualization and blood vessel stability. Our findings also suggest that disturbance in sphingolipid metabolism may be considered as a cause of pregnancy loss in humans. IntroductionEmbryonic implantation is a complex series of processes that establishes the connection between maternal and embryonic tissues and requires an intricate program of uterine preparation (1, 2). Very soon after implantation, which occurs in the mouse on day 4.5 postcoitum (pc) (day 0.5 - vaginal plug), endometrial stromal cells surrounding implanting blastocysts undergo dramatic transformation (decidualization), during which they proliferate and differentiate into decidual cells. Decidualization begins in the stromal region immediately surrounding the embryo (antimesometrial site). Next to the implanting blastocyst, thin, dense, avascular cell layers, called the primary decidual zone, are formed. Adjacent to the primary decidual zone, the broad secondary decidual zone is fully developed by day 6.5 pc, and is characterized by terminally differentiated decidual polyploidy with acquisition of large mono- or binucleated cells (3). The decidua provides a vascular network for nutrition and gas exchange for the developing embryo before a functional placenta is established (4). It also acts as a barrier to uncontrolled trophoblast proliferation.The sphingolipid metabolic pathway produces bioactive signaling metabolites as well as complex lipids that are utilized in membrane organization and structure. A very prominent signaling lipid is sphingosine-1-phosphate (S1P), which enhances cell survival and growth (5-8). Recent studies have demonstrated its physiologic importance in the development of the vascular and nervous system (9-12), the heart (13), and the immune system (14-16) by signaling through a family of G protein-coupled receptors designated S1P 1-5 . In contrast, 2 precursors of S1P,

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“…Sphingosine-1-phosphate (S1P) is part of a key group of signaling sphingolipids recognized to serve diverse roles in a variety of cellular processes, including apoptosis, migration, differentiation and proliferation in a variety of cell types, including endothelial cells, smooth muscle cells, mesenchymal stem cells and macrophages (8)(9)(10). S1P has been demonstrated to act as a ligand of G-protein-coupled receptors, namely S1P receptors (11).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the expression of sphingosine 1-phosphate 2 receptors regulates the differentiation of pre-adipocytes

Jeong

Moon

Park

2015

Molecular Medicine Reports

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Abstract. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator that regulates multiple signals through S1P receptors responsible for biological responses. In particular, the S1P 2 receptor has distinct roles in the S1P-mediated differentiation of certain cell types. The present study was the first, to the best of our knowledge, to report the role of the S1P 2 receptor in the adipocyte differentiation of 3T3-L1 pre-adipocytes. In order to investigate the influence of S1P 2 receptors in the anti-adipogenic effects of S1P, S1P 2 receptor silencing and overexpression of were used. S1P 2 overexpression with adenoviral vectors inhibited adipogenesis and inhibited the expression of peroxisome proliferator-activated receptor γ (PPARγ), adiponectin and CCAAT/enhancer binding protein-α, which were upregulated following incubation in differentiation media. Furthermore, S1P completely lost its ability to impair adipogenic differentiation following silencing of S1P 2 . Silencing of the S1P 2 receptor additionally blocked the downregulation of PPARγ protein and phospho-c-Jun N-terminal kinase protein induced by S1P treatment. In conclusion, the present study demonstrated that the S1P 2 receptor is a key signaling molecule in the S1P-dependent inhibition of adipogenic differentiation and additionally suggested that selective targeting of S1P 2 receptors may have clinical applications for the treatment of obesity.

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Sphingosine-1-phosphate inhibition of placental trophoblast differentiation through a Gi-coupled receptor response

Cited by 40 publications

References 40 publications

Maternal and Embryonic Control of Uterine Sphingolipid-Metabolizing Enzymes During Murine Embryo Implantation1

Maternal and Embryonic Control of Uterine Sphingolipid-Metabolizing Enzymes During Murine Embryo Implantation1

Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

Modulation of the expression of sphingosine 1-phosphate 2 receptors regulates the differentiation of pre-adipocytes

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