Hypoxia reduces expression and function of system A  amino acid transporters in cultured term human trophoblasts

Nelson, D. Michael; Smith, Steven D.; Furesz, T.C.; Sadovsky, Yoel; Ganapathy, Vadivel; Parvin, Curtis A.; Smith, Carl H.

doi:10.1152/ajpcell.00253.2002

Cited by 100 publications

(88 citation statements)

References 39 publications

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“…System A activity is also reduced in cytotrophoblast cells cultured in low oxygen tensions and this is associated with decreased expression of SLC38A1 and SLC38A2 mRNA (Nelson et al, 2003). Altered blood flow to the placenta in pregnancies associated with FGR and preeclampsia, discussed earlier in this chapter, leads to reduced oxygen delivery.…”

Section: Regulation Of System a By External Factorsmentioning

confidence: 81%

Placental nutrient supply and fetal growth

Desforges¹,

Sibley²

2010

Int. J. Dev. Biol.

146

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This review considers mechanisms by which transfer across the placenta takes place and how the capacity of the placenta to supply nutrients relates to fetal growth and vice versa. Blood flow through both uterine and umbilical circulations of the placenta, the structural properties of the placental exchange barrier and its related diffusional permeability, and the expression and activity of a wide range of transporter proteins in the syncytiotrophoblast, the transporting epithelium of the placenta, all need to be taken into account in considering placental supply capacity. We discuss the evidence that each of these factors affects, and is affected by, fetal growth rate and consider the regulatory mechanisms involved, with a particular focus on data that has emerged from study of the system A amino acid transporter. We consider that future work will build on the considerable foundation of knowledge regarding placental transfer mechanisms, as well as the other aspects of placental structure and function, to develop new diagnostic and therapeutic strategies for pregnancy complications, such as fetal growth restriction or overgrowth.

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Section: Regulation Of System a By External Factorsmentioning

confidence: 81%

Placental nutrient supply and fetal growth

Desforges¹,

Sibley²

2010

Int. J. Dev. Biol.

146

View full text Add to dashboard Cite

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“…28 Six hours of hypoxia reduced the substrate affinity of System A transporters in cultured human lung fibroblasts. 29 SNAT1 expression decreased in rat pup brains 24 h after hypoxia-ischaemia but increased 7 days later.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Hypoxia Augments L-Citrulline Transport By System A In The Newborn Piglet Pulmonary Circulation

Fike

Sidoryk‐Węgrzynowicz

Aschner

et al. 2012

B63. Experimental Models in Pulmonary Hypertension I

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AimsPulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of L-arginine from intracellular L-citrulline but do not express the enzymes needed for de novo L-citrulline synthesis. Hence, L-citrulline levels in PAECs are dependent on L-citrulline transport. Once generated, L-arginine can be converted to L-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to pulmonary hypertension, alters the transport of L-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets. Methods and resultsPAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and 14 C-L-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. 14 C-L-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased 14 C-L-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and L-citrulline levels in lungs of piglets with chronic hypoxia-induced pulmonary hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher L-citrulline levels than lungs from controls. ConclusionIncreased SNAT1 expression and the concomitant enhanced ability to transport L-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic hypoxia-induced pulmonary hypertension in newborns. ----------------------------------------------------------------------- KeywordsPulmonary hypertension † Sodium-coupled neutral amino acid transporters † Nitric oxide

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“…The functional role of SNAT2, a neutral amino acid transporter, has been extensively described in placental tissues of different species and in human placental cells in vitro (13,(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…Snat2 regulation is mediated by several factors (13,(16)(17)(18)(19), particularly hypoxia and amino acid extracellular concentrations. SNAT2 intron-1 is a noncoding region within the SNAT2 gene that spans 54 nucleotides and contains sequences that are able to respond to amino acid deficiency and activate SNAT2 gene expression (20).…”

mentioning

confidence: 99%

SNAT2 expression and regulation in human growth-restricted placentas

et al. 2013

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Background: Amino acid placental delivery is reduced in human intrauterine growth-restricted (IUGR) fetuses, and the activity of placental amino transporters has been consistently shown to be decreased in in vitro studies. We hypothesized lower placental expression and localization of sodium-coupled neutral amino acid transporter 2 (SNAT2 (also known as SLC38A2)), altered levels of intron-1 methylation, and altered distribution of single-nucleotide polymorphisms in human IUGR vs. normal pregnancies. Methods: We studied 88 IUGR and 84 control placentas from singleton pregnancies at elective caesarean section. SNAT2 expression was investigated by real-time PCR and immunohistochemistry. Intron-1 methylation levels were analyzed by pyrosequencing, and single-nucleotide polymorphism distribution was analyzed by allelic discrimination. results: mRNA levels were significantly decreased in IUGR placentas with reduced umbilical blood flows. Syncytiotrophoblast immunostaining was lower in IUGR placentas than in control placentas. Methylation levels were steadily low in both IUGR and control placentas. SNP genotype and allele frequencies did not differ between the two groups. conclusion: This is the first study investigating SNAT2 expression and regulation mechanisms in human IUGR placentas. We confirm previous results obtained in rats and cell cultures that support the fundamental role of SNAT2 in fetal growth and well-being, as well as a possible role of oxygen levels in regulating SNAT2 expression, indicating the relevance of hypoxia in IUGR.

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Hypoxia reduces expression and function of system A amino acid transporters in cultured term human trophoblasts

Cited by 100 publications

References 39 publications

Placental nutrient supply and fetal growth

Placental nutrient supply and fetal growth

Prolonged Hypoxia Augments L-Citrulline Transport By System A In The Newborn Piglet Pulmonary Circulation

SNAT2 expression and regulation in human growth-restricted placentas

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