Abstract
BackgroundAnticoagulants, e.g. low-molecular weight heparins (LMWHs) and acetylsalicylic acid (ASA) are prescribed to women at risk for pregnancy complications that are associated with impaired placentation and placental hypoxia. Beyond their role as anticoagulants these compounds exhibit direct effects on trophoblast but their impact on placental function is unknown. The amino acid transport systems A and L, which preferably transfer essential amino acids, are well-described models to study placental nutrient transport. We aimed to examine the effect of hypoxia, LMWHs and ASA on the activity of the placental amino acid transport systems A and L and associated signalling mechanisms.MethodsThe uptake of C14-MeAIB (system A) or H3-leucin (system L) was investigated after incubation of primary villous fragments isolated from term placentas. Villous tissue was incubated at 2% O2 (hypoxia), 8% O2 and standard culture conditions (21% O2) or at 2% O2 and 21% O2 with dalteparin or ASA. Activation of the JAK/STAT or mTOR signalling pathways was determined by Western analysis of total and phosphorylated STAT3 or Raptor.ResultsHypoxia decreased system A mediated MeAIB uptake and increased system L mediated leucine uptake compared to standard culture conditions (21% O2). This was accompanied by an impairment of STAT3 and a stimulation of Raptor signalling. System L activity increased at 8% O2. Dalteparin treatment reduced system A and system L activity under normoxic conditions and ASA (1 mM) decreased system A and L transporter activity under normoxic and hypoxic conditions.ConclusionsOur data underline the dependency of placental function on oxygen supply. LMWHs and ASA are not able to reverse the effects of hypoxia on placental amino acid transport. These findings and the uncovering of the signalling mechanisms in more detail will help to understand the impact of LMWHs and ASA on placental function and fetal growth.
Highlights
Adequate placental development during pregnancy is a major determinant of pregnancy outcome
Hypoxic culture conditions (2% O2) decreased system A amino acid transporter activity by 27% in placental villous explants after 2 h compared to standard culture conditions (21% O2), (0.7360.07, p,0.001, n = 22, figure 1A)
In contrast to system A, the transporter activity of system L significantly increased by 42% under hypoxic conditions compared to an oxygen level of 21% O2 (1.4260.13, p = 0.01, n = 22, figure 1B)
Summary
Adequate placental development during pregnancy is a major determinant of pregnancy outcome. Several changes in placental morphology and function have been described in pregnancies complicated by preeclampsia, fetal intrauterine growth restriction (IUGR), placental infarction and recurrent abortions [1] Among these alterations, impaired invasion of the extravillous trophoblast and failed vascular remodeling of the maternal spiral arteries is thought to result in impaired uterine blood flow to the developing placenta, contributing to intermittent hypoxia and placental dysfunction [2,3,4]. Anticoagulants, e.g. low-molecular weight heparins (LMWHs) and acetylsalicylic acid (ASA) are prescribed to women at risk for pregnancy complications that are associated with impaired placentation and placental hypoxia Beyond their role as anticoagulants these compounds exhibit direct effects on trophoblast but their impact on placental function is unknown. We aimed to examine the effect of hypoxia, LMWHs and ASA on the activity of the placental amino acid transport systems A and L and associated signalling mechanisms
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