Sphingolipid Signature of Human Feto-Placental Vasculature in Preeclampsia.

Ilaria Del Gaudio,Christian Wadsack,Annarita Di Lorenzo,Linda Sasset

doi:10.3390/ijms21031019

Ilaria Del Gaudio, Christian Wadsack + Show 2 more

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https://doi.org/10.3390/ijms21031019

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Abstract

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.

Highlights

Preeclampsia (PE) is characterized by profound morphological and functional modifications in the arterial vessels of the uterus and the placenta
The aim of this study is to investigate whether PE affects the key players of the sphingolipid metabolism to impact their signature in the feto-placental vasculature, which plays a critical role in regulating angiogenesis, vasomotor tone, and placental perfusion, pivotal to fetal development
The quantification of single ceramide species showed that, whereas an overall trend towards reduced levels could be observed in different species, only C20:0-cer was significantly decreased in PE compared to placental arteries from normotensive (PN) chorionic arteries (Figure 1A(b),(c))

Summary

Introduction

Preeclampsia (PE) is characterized by profound morphological and functional modifications in the arterial vessels of the uterus and the placenta. Poor vascular adaptions in the mother and an inflammatory intrauterine environment during pregnancy, affect the functionality of the feto-placental endothelium. This does lead to pregnancy-related maternal and fetal morbidities and to adverse outcomes for the offspring later in life, e.g., increased risk to develop hypertension (3-fold) and cardiovascular disease (2-fold) later in life [1,2,3]. PE has an incidence of 3–5% of pregnancies in the United States and up to 10% of pregnancies worldwide [4], representing the leading cause of maternal and fetal morbidity and mortality. An association between impaired lipid metabolism and loss of endothelium functionality has been proposed in women who develop PE [6]

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