sphingosine-1-phosphate and Pre-Eclampsia

Recent progress in lipid research has unveiled new biologic roles for lysophospholipids as mediators of intercellular signaling. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are representative lysophospholipids. Accumulating evidence suggests that, acting as intercellular mediators, these and other lysophospholipids may play important roles in physiological and pathological situations. This review discusses the possible involvement of LPA and S1P in reproductive processes, with a focus on the regulatory mechanisms of pregnancy maintenance. As LPA promotes prostaglandin synthesis, mediators in the LPA pathway may also play a significant role in implantation and parturition. S1P signaling is thought to be essential in vascular formation within the uteroplacental unit and in fetomaternal immunologic interactions. Derangements in either one of these lysophospholipid signaling pathways could result in pregnancy complications that may include implantation failure, preeclampsia, and preterm labor.

Topics: Endometrium; Female; Humans; Lysophospholipids; Maternal-Fetal Exchange; Neovascularization, Physiologic; Obstetric Labor, Premature; Ovary; Parturition; Placenta; Pre-Eclampsia; Pregnancy; Prostaglandins; Signal Transduction; Sphingosine

Sphingolipids like sphingosine-1-phosphate (S1P) have been implicated in the pathophysiology of pre-eclampsia. We hypothesized that plasma S1P would be increased in women at high risk of developing pre-eclampsia who subsequently develop the disease. Low circulating placental growth factor (PlGF) is known to be associated with development of pre-eclampsia; so further, we hypothesized that increased S1P would be associated with concurrently low PlGF. This was a case-control study using stored maternal blood samples from 14 to 24 weeks of pregnancy, collected from 95 women at increased risk of pre-eclampsia. Pregnancy outcome was classified as uncomplicated, preterm pre-eclampsia (<37 weeks), or term pre-eclampsia. Plasma lipids were extracted and analyzed by ultraperformance liquid chromatography coupled to electrospray ionization MS/MS to determine concentrations of S1P and sphingosine. Median plasma S1P was 0.339 nmol/ml, and median sphingosine was 6.77 nmol/l. There were no differences in the plasma concentrations of S1P or sphingosine in women who subsequently developed pre-eclampsia, no effect of gestational age, fetal sex, ethnicity, or the presence of pre-existing hypertension. There was a correlation between S1P and sphingosine plasma concentration (P < 0.0001). There was no relationship between S1P or sphingosine with PlGF. Previous studies have suggested that plasma S1P may be a biomarker of pre-eclampsia. In our larger study, we failed to demonstrate there are women at high risk of developing the disease. We did not show a relationship with known biomarkers of the disease, suggesting that S1P is unlikely to be a useful predictor of the development of pre-eclampsia later in pregnancy.

Topics: Biomarkers; Case-Control Studies; Female; Humans; Infant, Newborn; Male; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Sphingosine; Tandem Mass Spectrometry

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

Topics: Actins; Animals; Female; Humans; Lysophospholipids; Mice; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Proto-Oncogene Proteins c-yes; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Trophoblasts

Preeclampsia (PE), a hypertensive multisystem disorder, can lead to increased maternal and fetal mortality and morbidity. Sphingosine‑1‑phosphate (S1P) plays various roles, depending on the cell type, by binding to S1P receptors (S1PR). The present study evaluated the changes of S1PRs and investigated the potential role of S1PRs in pregnancy‑induced hypertension. PE rats were established by reduced uterine perfusion pressure. The involvement of S1PR2 was evaluated using JTE‑013, a specific S1PR2 antagonist, in PE rats. After the treatment, inflammatory cytokines were evaluated using enzyme linked immunosorbent assay, and the expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) activation and endothelial nitric oxide synthase (eNOS) were evaluated by reverse transcription‑quantitative PCR and western blotting. Results showed that S1PR2, but not S1PR1 and S1PR3, was significantly increased in the serum and placenta tissues of PE rats. Notably, JTE‑013 significantly decreased blood pressure, attenuated infiltration of inflammatory cells and decreased inflammation, as indicated by the decreased expression of inflammatory cytokines, including tumor necrosis factor‑α, interleukin‑1β (IL‑1β) and IL‑6, in placental tissues. Mechanistic studies demonstrated that JTE‑013 significantly increased the expression of VEGF and decreased the expression of fms‑like tyrosine kinase 1 in placental tissue. Furthermore, JTE‑013 prevented iNOS activation and increased eNOS in placental tissue. In summary, the present study demonstrated that S1PR2 contributed to hypertension and angiogenesis imbalance in PE rats.

Topics: Angiogenesis Inducing Agents; Animals; Blood Pressure; Cytokines; Female; Interleukin-1beta; Lysophospholipids; Neovascularization, Pathologic; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Sphingosine; Sphingosine-1-Phosphate Receptors; Vascular Endothelial Growth Factor A

Bioactive sphingolipids are emerging as key regulators of vascular function and homeostasis. While most of the clinical studies have been devoted to profile circulating sphingolipids in maternal plasma, little is known about the role of the sphingolipid at the feto-placental vasculature, which is in direct contact with the offspring circulation. Our study aims to compare the sphingolipid profile of normal with preeclamptic (PE) placental chorionic arteries and isolated endothelial cells, with the goal of unveiling potential underlying pathomechanisms in the vasculature. Dihydrosphingosine and sphingomyelin (SM) concentrations (C16:0-, C18:0-, and C24:0- sphingomyelin) were significantly increased in chorionic arteries of preeclamptic placentas, whereas total ceramide, although showing a downward trend, were not statistically different. Moreover, RNA and immunofluorescence analysis showed impaired sphingosine-1-phosphate (S1P) synthesis and signaling in PE vessels. Our data reveal that the exposure to a deranged maternal intrauterine environment during PE alters the sphingolipid signature and gene expression on the fetal side of the placental vasculature. This pathological remodeling consists in increased serine palmitoyltransferase (SPT) activity and SM accrual in PE chorionic arteries, with concomitance impairment endothelial S1P signaling in the endothelium of these vessels. The increase of endothelial S1P phosphatase, lyase and S1PR2, and blunted S1PR1 expression support the onset of the pathological phenotype in chorionic arteries.

Topics: Arteries; Ceramides; Chorion; Endothelial Cells; Endothelium, Vascular; Female; Fetus; Gene Expression; Humans; Lysophospholipids; Maternal-Fetal Exchange; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Signal Transduction; Sphingolipids; Sphingomyelins; Sphingosine