Sphingolipid Signature of Human Feto-Placental Vasculature in Preeclampsia

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.

Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth

“…Sphingomyelins are plasma membrane components, as well as signaling sphingolipids. An altered distribution of sphingomyelin and other sphingolipid species has been shown to play an important role in preeclampsia [ 31 , 32 , 33 ]. Sphingomyelin can also be degraded into phosphocholine and ceramide via SMPD2 [ 34 ].…”

Involvement of Ceramide Metabolism in Cerebral Ischemia

“…Accordingly, disruption of sphingolipid metabolism, with an increase in SPT activity, augments Cer-induced autophagy in preeclampsia ( Melland-Smith et al, 2015 ). In this regard, sphingolipid profiling of human fetoplacental vasculature in preeclampsia demonstrated high levels of Cer and dhCer, due to an upregulation of SPT, which was reversed by Nogo-B activation ( del Gaudio et al, 2020 ). Nogo-B protein (also called reticulon-4B) is ubiquitously expressed in peripheral tissues, being implicated in several functions such as inflammation or vasculature remodeling.…”

Lipidomic Analysis of TRPC1 Ca2+-Permeable Channel-Knock Out Mouse Demonstrates a Vital Role in Placental Tissue Sphingolipid and Triacylglycerol Homeostasis Under Maternal High-Fat Diet

“…Thus, the greater concentrations of SM 34:1 in TRPC1 -/- -HF placentae relative to WT-HF at both developmental periods suggests perturbation of sphingolipid homeostasis independent of gestational status. This is an important finding because Del Gaudio and colleagues noted accumulation of SM 34:1, SM 36:1 and SM 42:1 to the endothelium of feto-placental blood vessels from preeclamptic placentae, indicating a link between SM-accumulation and placental vascular development ( 37 ).…”