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J Clin Endocrinol Metab. 2015 Jul;100(7):E986-96. doi: 10.1210/jc.2015-1288. Epub 2015 May 5.

Aberrant TGFβ Signalling Contributes to Dysregulation of Sphingolipid Metabolism in Intrauterine Growth Restriction.

Author information

1
The Lunenfeld-Tanenbaum Research Institute (S.C., Y.Y., J.X., J.S., A.T., I.C.), Mount Sinai Hospital, Toronto, Canada M5T 3H7; Departments of Obstet Gynecol (Y.Y., I.C.), Physiology (S.C., M.P., I.C.), and Pediatrics (M.P.), Institute of Medical Sciences University of Toronto (M.P., I.C.), Toronto, Canada; The Hospital for Sick Children (L.E., M.P.), Toronto, Canada M5G 1X8; and Department of Obstet Gynecol (T.T.), University of Turin, Turin, Italy 10126.

Abstract

CONTEXT:

Sphingolipids function as key bioactive mediators that regulate cell fate events in a variety of systems. Disruptions in sphingolipid metabolism characterize several human pathologies.

OBJECTIVE:

In the present study we examined sphingolipid metabolism in intrauterine growth restriction (IUGR), a severe disorder complicating 4-7% of pregnancies at increased risk of perinatal morbidity and mortality, which is characterized by placental dysfunction and augmented trophoblast cell death rates.

DESIGN, SETTING, AND PARTICIPANTS:

Placentae from early severe IUGR with documented abnormal umbilical artery Doppler defined as absence or reverse of end diastolic velocity and a birth weight below the fifth percentile for gestational age were collected (n = 58). Placental tissues obtained from healthy, age-matched preterm and term deliveries (n = 46; TC, n=28) were included as controls.

RESULTS:

Sphingolipid analysis by tandem mass spectrometry revealed elevated sphingosine and decreased ceramide levels in placentae from pregnancies complicated by IUGR relative to age-matched controls. Sphingosine accumulation was due to accelerated ceramide breakdown via increased acid ceramidase (ASAH1) expression/activity caused by augmented TGFβ signalling via the ALK5/SMAD2 pathway. In addition, a marked reduction in sphingosine kinase 1 (SPHK1) expression/activity due to impaired TGFβ signalling via ALK1/SMAD1 contributed to the sphingosine buildup in IUGR. Of clinical significance, ALK/SMAD signalling pathways were differentially altered in IUGR placentae.

CONCLUSIONS:

Altered TGFβ signalling in IUGR placentae causes dysregulation of sphingolipid metabolism, which may contribute to the increased trophoblast cell death typical of this pathology.

PMID:
25942476
DOI:
10.1210/jc.2015-1288
[Indexed for MEDLINE]
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