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


METHODS
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.
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.
Sarah
S
Chauvin
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.
Yoav
Y
Yinon
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.
Jing
J
Xu
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.
Leonardo
L
Ermini
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.
Julien
J
Sallais
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.
Andrea
A
Tagliaferro
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.
Tullia
T
Todros
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.
Martin
M
Post
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.
Isabella
I
Caniggia
D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D050356:Lipid Metabolism / Q000502:physiology; D052439:Lipid Metabolism Disorders / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*; D047929:Term Birth / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D013107:Sphingolipids; D016212:Transforming Growth Factor beta