Antenatal Corticosteroids Impact the Inflammatory Rather Than the Antiangiogenic Profile of Women With Preeclampsia

Nayeri, Unzila A.; Buhimschi, Irina A.; Laky, Christine; Cross, Sarah; Duzyj, Christina M.; Ramma, Wenda; Sibai, Bahaeddine M; Funai, Edmund F.; Ahmed, Asif; Buhimschi, Catalin S.

doi:10.1161/hypertensionaha.114.03173

Cited by 21 publications

(12 citation statements)

References 43 publications

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“…Despite silencing or overexpressing genes involved in the NFκB pathway in cytotrophoblasts, there was no change in sFlt-1 or sENG secretion suggesting the NFκB pathway may not be involved in their regulation. This is consistent with reports demonstrating the administration of corticosteroids, known to inhibit NFκB [37], do not change serum sFlt-1 and sENG levels in patients with preeclampsia [38]. Furthermore, silencing HO-1 did not affect the ability of sulfasalazine to reduce sFlt-1 secretion from cytotrophoblasts.…”

Section: Discussionsupporting

confidence: 92%

Sulfasalazine reduces placental secretion of antiangiogenic factors, up-regulates the secretion of placental growth factor and rescues endothelial dysfunction

et al. 2019

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Background Preeclampsia is a major complication of pregnancy with no medical treatment. It is associated with placental oxidative stress, hypoxia and inflammation leading to soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion and reduced placental growth factor (PlGF). This results in widespread endothelial dysfunction causing hypertension and multisystem organ injury. Sulfasalazine is an anti-inflammatory and antioxidant medication used to treat autoimmune disease. Importantly, it is safe in pregnancy. We examined the potential of sulfasalazine to quench antiangiogenic factors and endothelial dysfunction and increase angiogenic factor secretion. Methods We performed functional experiments using primary human pregnancy tissues to examine the effects of sulfasalazine on sFlt-1, sENG and PlGF secretion. Sulfasalazine is known to inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and upregulate heme-oxygenase 1 (HO-1) thus we explored the effect of these transcription factors on sFlt-1 secretion from human cytotrophoblasts. We examined the ability of sulfasalazine to reduce key markers of endothelial dysfunction and dilate whole blood vessels. Findings We demonstrate sulfasalazine administration reduces sFlt-1 and sENG and upregulates PlGF secretion from human placental tissues. Furthermore sulfasalazine mitigates endothelial dysfunction in several in vitro/ex vivo assays. It enhanced endothelial cell migration and proliferation, promoted blood vessel dilation (vessels obtained from women at caesarean section) and angiogenic sprouting from whole blood vessel rings. The effect of sulfasalazine on the secretion of sFlt-1 was not mediated through either the NFkB or HO-1 pathways. Interpretation We conclude that sulfasalazine reduces sFlt-1 and sENG secretion and endothelial dysfunction and upregulates PlGF. Sulfasalazine has potential to treat or prevent preeclampsia and warrants investigation in clinical trials. Funding This work was funded by The National Health and Medical Research Council of Australia (NHMRC; #1048707, #1046484. #1101871, #1064845), an Arthur Wilson RANZCOG scholarship and a Norman Beischer Medical Research Foundation grant. FB was supported by a NHMRC Early Career Fellowship (NHMRC #1142636). NJH was supported by a CR Roper Research Fellowship. The NHMRC provided salary support (#1136418 to ST #1062418 to TKL, #1064845 to SS). The funders had no role in study design, data collection, analysis, decision to publish or the preparation of the manuscript.

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Section: Discussionsupporting

confidence: 92%

Sulfasalazine reduces placental secretion of antiangiogenic factors, up-regulates the secretion of placental growth factor and rescues endothelial dysfunction

et al. 2019

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“…During admission, the majority of these patients did receive regular antihypertensive therapy and all of our patients were given steroids for fetal maturation. Antihypertensive therapy 35 and steroids 36 have not been shown to affect preeclampsia disease progression or the secretion of antiangiogenic factors. The blood pressure seemed to stabilize without the need for increasing regular antihypertensive therapy in 3 of 4 patients although there were no new symptoms and no biochemical evidence of new onset involvement of other organ systems, such as the liver and the hematological system.…”

Section: Discussionmentioning

confidence: 99%

Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia

et al. 2015

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Abstract-Preeclampsia is a major pregnancy complication where excess placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin causes maternal endothelial and multisystem organ injury. Clinical trials have commenced examining whether pravastatin can be used to treat preeclampsia. However, the preclinical evidence supporting pravastatin as a treatment is limited to animal models, with almost no studies in human tissues. Therefore, we examined whether pravastatin reduced sFlt-1 and soluble endoglin secretion and decreased endothelial dysfunction in primary human tissues. Pravastatin reduced sFlt-1 secretion from primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia. It increased soluble endoglin secretion from endothelial cells but did not change secretion from placental explants. The regulation of sFlt-1 by pravastatin seemed to be mediated via the 3-hydroxy-3-methylglutaryl-coenzyme A reductase cholesterol synthesis pathway. Pravastatin also reduced markers of endothelial dysfunction, including vascular cell adhesion molecule-1 expression and leukocyte adhesion on endothelial cells and increased endothelial cell migration and invasion. We also treated 4 patients with preterm preeclampsia presenting at <30 weeks of gestation with daily pravastatin. Pravastatin seemed to stabilize blood pressure, proteinuria, and serum uric acid levels. Furthermore, serum sFlt-1 levels decreased. We collected the placentas at delivery and found that pravastatin reduced sFlt-1 secretion. These results indicate that pravastatin reduced sFlt-1 and soluble endoglin production and decreased endothelial dysfunction in primary human tissues. We also present pilot data, suggesting that pravastatin can stabilize clinical and biochemical features of preterm preeclampsia. Our data obtained in human tissues support the concept that pravastatin is a candidate therapeutic for preeclampsia. Clinical Trial Registration-URL: http://www.anzctr.org.au. Unique identifier: ACTRN12613000268741.

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“…In many cases the gestational age at which the samples were collected were not clearly specified. Details regarding medication during pregnancy is important as preeclamptic women, particularly in severe cases, often receive antepartum corticosteroids for fetal lung maturation during birth, which may affect protein secretion in the circulation of the mother [70]. Patients included in this analysis are of mixed background.…”

Section: Discussionmentioning

confidence: 99%

Using proteomics to advance the search for potential biomarkers for preeclampsia: A systematic review and meta-analysis

et al. 2019

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Background Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality worldwide. Although predictive multiparametric screening is being developed, it is not applicable to nulliparous women, and is not applied to low-risk women. As PE is considered a heterogenous disorder, it is unlikely that any single multiparametric screening protocol containing a small group of biomarkers could have the required accuracy to predict all PE subgroups. Given the etiology of PE is complex and not fully understood, it begs the question, whether the search for biomarkers based on the predominant view of impaired placentation involving factors predominately implicated in angiogenesis and inflammation, has been too limiting. Here we highlight the enormous potential of state-of-the-art, high-throughput proteomics, to provide a comprehensive and unbiased approach to biomarker identification. Methods and findings Our literature search identified 1336 articles; after review, 45 studies with proteomic data from PE women that were eligible for inclusion. From 710 proteins with altered abundance, we identified 13 common circulating proteins, some of which had not been previously considered as prospective biomarkers of PE. An additional search of the literature for original publications testing any of the 13 common proteins using non-proteomic techniques was also undertaken. Strikingly, 9 of these common proteins had been independently evaluated in PE studies as potential biomarkers. Conclusion This study highlights the potential of using high-throughput data sets, which are comprehensive and without bias, to identify a profile of proteins that may improve predictions of PE and understanding of its etiology. We bring to the attention of the medical and research communities that the strengths and advantages of using data from high-throughput studies for biomarker discovery would be increased dramatically, if first and second trimester samples were collected for proteomics, and if standardized guidelines for patient reporting and data collection were implemented.

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Antenatal Corticosteroids Impact the Inflammatory Rather Than the Antiangiogenic Profile of Women With Preeclampsia

Cited by 21 publications

References 43 publications

Sulfasalazine reduces placental secretion of antiangiogenic factors, up-regulates the secretion of placental growth factor and rescues endothelial dysfunction

Sulfasalazine reduces placental secretion of antiangiogenic factors, up-regulates the secretion of placental growth factor and rescues endothelial dysfunction

Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia

Using proteomics to advance the search for potential biomarkers for preeclampsia: A systematic review and meta-analysis

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