Poster Session 1 - R5
1,2Isidora Rovic, 2Han Li, 1,2Katherine Szelag, 2,3Andrea Jurisicova
1 Dept. of Physiology, University of Toronto; 2 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada, 3 Dept. of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada
Intrauterine growth restriction (IUGR), a condition in which fetal growth is compromised during pregnancy, is one of the leading causes of fetal and neonatal morbidity and mortality. IUGR is often due to placental insufficiency, where the placenta is unable to deliver an adequate supply of nutrients and oxygen to the developing fetus. The molecular mechanisms underlying placental insufficiency and IUGR are still being elucidated. In the present study, we demonstrate that acid sphingomyelinase (aSMase), a lipid hydrolase enzyme involved in sphingolipid metabolism, is critical for normal placental development and function. Fetuses deficient for aSMase (KO) display markedly decreased weights in late gestation and decreased neonatal weights, compared to WT fetuses. In addition, KO placentas display structural abnormalities, including decreased surface area of labyrinth, as well as decreased mRNA expression of placental lactogen I (PL-I), a marker of invasive primary trophoblast giant cells (P-TGC) which are important for the successful implantation and invasion of the placenta into the maternal lining. Further analysis of labyrinth morphology revealed a thicker interhemal membrane (lining between maternal and fetal blood spaces) in KO placentas, which could impede the exchange of nutrients and gases between the mother and fetus. In addition, analysis of sphingolipid metabolites by mass spectrometry revealed a three-fold decrease of sphingosine-1-phosphate (S1P), a sphingolipid important for promoting vascularization, in KO placentas. Finally, immunofluorescence and western blot analysis of KO placentas revealed defective autophagy, and increased nuclear localization of transcription factor EB (TFEB) in KO trophoblast cells, indicative of cellular stress. In conclusion, aSMase-deficient fetuses display an IUGR-like phenotype, in part due to abnormal placental development. The morphological and functional abnormalities of KO placentas can be partially attributed to decreased levels of S1P and defective autophagy, which is important for normal development of the placenta. This study proposes aSMase-deficient mice as a novel model of IUGR, and can aid in the understanding of molecular events which lead to IUGR and placental pathologies in humans.