Placental Production of Eicosanoids and Sphingolipids in Women Who Developed Preeclampsia on Low-Dose Aspirin

Walsh, Scott W.; Reep, Daniel T.; Alam, Shamsul; Washington, Sonya L.; Dulaimi, Marwah Al; Lee, Stephanie M; Springel, Edward; Strauss, Jerome F.; Stephenson, Daniel J.; Chalfant, Charles E.

doi:10.1007/s43032-020-00234-2

Cited by 10 publications

(15 citation statements)

References 61 publications

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“…We also found evidence that maternal ingestion of aspirin attenuated placental oxidative stress. Two of the most abundant isoprostanes, 8-isoprostane (8-iso PGF2a) and 5-isoprostane (5-iPF2a), which are significantly elevated in placentas of preeclamptic women [46,47], were not elevated in our study of women who developed preeclampsia while on aspirin therapy (Figure 5) [39]. Isoprostanes are accurate markers of endogenous lipid peroxidation.…”

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 58%

“…They are not cyclooxygenase metabolites, and so, are not affected by aspirin. The placenta produced 42 sphingolipids, 5 of which were abnormal in women with severe preeclampsia [39]. All sphingolipids that were abnormal were significantly increased compared to normal pregnancy, including major C:18 forms.…”

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 99%

“…As part of the NICHD Human Placental Project, we undertook a comprehensive evaluation of placental lipids in women with normal pregnancy (NP) and women at risk for preeclampsia who were prescribed aspirin [39]. We found the placenta is a rich source of eicosanoids.…”

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 99%

“…HETEs are lipoxygenase metabolites of arachidonic acid, and they are, therefore, not affected by low-dose aspirin. The placenta produced four HETEs, two of which, 15-HETE and 20-HETE, were significantly elevated in women who delivered preterm with severe preeclampsia (Figure 8) [39]. Both of these HETEs cause inflammation [54][55][56][57][58][59][60][61], and placental pathologic features of preterm preeclampsia are consistent with chronic inflammation [62].…”

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 99%

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The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

Walsh

Strauss

2021

IJMS

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The road to low-dose aspirin therapy for the prevention of preeclampsia began in the 1980s with the discovery that there was increased thromboxane and decreased prostacyclin production in placentas of preeclamptic women. At the time, low-dose aspirin therapy was being used to prevent recurrent myocardial infarction and other thrombotic events based on its ability to selectively inhibit thromboxane synthesis without affecting prostacyclin synthesis. With the discovery that thromboxane was increased in preeclamptic women, it was reasonable to evaluate whether low-dose aspirin would be effective for preeclampsia prevention. The first clinical trials were very promising, but then two large multi-center trials dampened enthusiasm until meta-analysis studies showed aspirin was effective, but with caveats. Low-dose aspirin was most effective when started <16 weeks of gestation and at doses >100 mg/day. It was effective in reducing preterm preeclampsia, but not term preeclampsia, and patient compliance and patient weight were important variables. Despite the effectiveness of low-dose aspirin therapy in correcting the placental imbalance between thromboxane and prostacyclin and reducing oxidative stress, some aspirin-treated women still develop preeclampsia. Alterations in placental sphingolipids and hydroxyeicosatetraenoic acids not affected by aspirin, but with biologic actions that could cause preeclampsia, may explain treatment failures. Consideration should be given to aspirin’s effect on neutrophils and pregnancy-specific expression of protease-activated receptor 1, as well as additional mechanisms of action to prevent preeclampsia.

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Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 58%

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 99%

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 99%

Section: Does Low-dose Aspirin Affect the Placenta?mentioning

confidence: 99%

See 2 more Smart Citations

The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

Walsh

Strauss

2021

IJMS

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“…The striking differences in transcriptomes of maternal neutrophils suggest that MPE and SPE result from different underlying pathophysiological mechanisms of disease. This idea is supported by a recent comprehensive evaluation of placental lipids in women who developed preeclampsia on low-dose aspirin therapy [ 18 ]. Women who developed SPE preterm had significant elevations in non-aspirin-sensitive eicosanoids and sphingolipids with biological actions that could cause PE, but the lipid profile in women who developed MPE did not show these elevations and their lipid profile was no different than women with normal pregnancy.…”

Section: Discussionmentioning

confidence: 96%

Patterns of Maternal Neutrophil Gene Expression at 30 Weeks of Gestation, but Not DNA Methylation, Distinguish Mild from Severe Preeclampsia

Walsh

Dulaimi

Archer

et al. 2021

IJMS

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Neutrophils are activated and extensively infiltrate blood vessels in preeclamptic women. To identify genes that contribute to neutrophil activation and infiltration, we analyzed the transcriptomes of circulating neutrophils from normal pregnant and preeclamptic women. Neutrophils were collected at 30 weeks’ gestation and RNA and DNA were isolated for RNA sequencing and 5-hydroxy-methylcytosine (5-hmC) sequencing as an index of dynamic changes in neutrophil DNA methylation. Women with normal pregnancy who went on to develop mild preeclampsia at term had the most uniquely expressed genes (697) with 325 gene ontology pathways upregulated, many related to neutrophil activation and function. Women with severe preeclampsia who delivered prematurely had few pathways up- or downregulated. Cluster analysis revealed that gene expression in women with severe preeclampsia was an inverse mirror image of gene expression in normal pregnancy, while gene expression in women who developed mild preeclampsia was remarkably different from both. DNA methylation marks, key regulators of gene expression, are removed by the action of ten-eleven translocation (TET) enzymes, which oxidize 5-methylcytosines (5mCs), resulting in locus-specific reversal of DNA methylation. DNA sequencing for 5-hmC revealed no differences among the three groups. Genome-wide DNA methylation revealed extremely low levels in circulating neutrophils suggesting they are de-methylated. Collectively, these data demonstrate that neutrophil gene expression profiles can distinguish different preeclampsia phenotypes, and in the case of mild preeclampsia, alterations in gene expression occur well before clinical symptoms emerge. These findings serve as a foundation for further evaluation of neutrophil transcriptomes as biomarkers of preeclampsia phenotypes. Changes in DNA methylation in circulating neutrophils do not appear to mediate differential patterns of gene expression in either mild or severe preeclampsia.

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Pregnancy-specific expression of protease-activated receptor 1: a therapeutic target for prevention and treatment of preeclampsia?

Walsh

Strauss

2022

American Journal of Obstetrics and Gynecology

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Placental Production of Eicosanoids and Sphingolipids in Women Who Developed Preeclampsia on Low-Dose Aspirin

Cited by 10 publications

References 61 publications

The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

Patterns of Maternal Neutrophil Gene Expression at 30 Weeks of Gestation, but Not DNA Methylation, Distinguish Mild from Severe Preeclampsia

Pregnancy-specific expression of protease-activated receptor 1: a therapeutic target for prevention and treatment of preeclampsia?

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