Aberrant TGFβ signalling contributes to dysregulation of sphingolipid metabolism in intrauterine growth restriction

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 complicating4-7%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 agematched 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.