Norepinephrine Transporter (NET), Serotonin Transporter (SERT), Vesicular Monoamine Transporter (VMAT2) and Organic Cation Transporters (OCT1, 2 and EMT) in Human Placenta from Pre-eclamptic and Normotensive Pregnancies

Bottalico, Barbara; Larsson, Inger; Brodszki, Jana; Hernández‐Andrade, Edgar; Casslén, Bertil; Maršál, Karel; Hansson, Stefan R.

doi:10.1016/j.placenta.2003.10.017

Cited by 95 publications

(63 citation statements)

References 49 publications

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“…In this regard, the mRNA for the serotonin transporter has been detected in the chorionic villa of human placenta. 36 Several lines of evidence have implicated serotonin as a mediator in the genesis of preeclampsia. Plasma serotonin concentration and the urinary excretion of serotonin metabolites are increased in preeclamptic women and the catalytic efficiency of the expressed monoamine oxidase-A, the major factor in the regulation of serotonin levels in pregnancy, is reduced in preeclamptic placenta.…”

Section: Discussionmentioning

confidence: 99%

Pregnant Rats Treated With a Serotonin Precursor Have Reduced Fetal Weight and Lower Plasma Volume and Kallikrein Levels

et al. 2007

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Abstract-Pregnant women with preeclampsia have increased serotonin levels, suggesting a possible role of this amine in abnormal pregnancy. With the hypothesis that an increase in serotonin would reduce volume expansion and cause fetal growth restriction, we evaluated the maternal and fetal effects of the administration of the serotonin precursor 5-hidroxytryptophan (5-HTP) to Sprague-Dawley rats. At pregnancy day 13 (nϭ19) or in random cycle nonpregnant rats (nϭ10), animals were assigned to a single injection of 5-HTP (100 mg/kg IP) or to a control group. Animals were studied at day 21, after overnight urinary collection. Additional pregnant rats received ketanserin (1 mg/kg), a 5-HT 2 receptor antagonist, 1 hour before 5-HTP injection. In pregnant rats, 5-HTP lowered plasma volume (control: 22Ϯ1.1; 5-HTP: 17Ϯ0.7 mL; PϽ0.001) and creatinine clearance, whereas serum creatinine and urinary protein excretion were increased; no changes were observed in nonpregnant rats. Systolic blood pressure did not change significantly. Urinary kallikrein activity and plasma aldosterone levels decreased only in pregnant animals. Fetal (control: 5.5Ϯ0.1; 5-HTP: 4.2Ϯ0.2 g; PϽ0.001) and placental weights were reduced. In nonpregnant and pregnant animals, 5-HTP caused profound renal morphological alterations and decreased kallikrein immunostaining. Preadministration of ketanserin abolished all of the changes associated with the use of 5-HTP. These data indicate that the administration of a serotonin precursor to pregnant rats limits plasma volume expansion and fetal growth via 5-HT 2 receptors, suggesting a possible role for serotonin in abnormal pregnancy. We postulate that an increased vascular resistance, both at the placental and renal levels, mediates these effects. Key Words: preeclampsia/pregnancy Ⅲ experimental models Ⅲ acute kidney failure Ⅲ kallikrein Ⅲ aldosterone Ⅲ plasma volume Ⅲ serotonin N ormal pregnancy, in humans and other mammals, is characterized by a significant reduction in systemic vascular resistance associated with lower arterial blood pressure, increased cardiac output, stimulation of the renin-angiotensin system, and plasma volume expansion. 1-3 These changes cause an important increment in uteroplacental blood flow, allowing normal fetal growth.In previous studies we have observed that pregnancy complications, such as fetal growth restriction or preeclampsia, are associated with reduced plasma volume expansion, increased vascular resistance, and lower levels of plasma renin activity, plasma aldosterone, and urinary kallikrein activity. 4,5 In preeclampsia an increased platelet aggregation has been described, with a consequent increment in serotonin (5-hydroxytryptamine; 5-HT) levels. 6 Serotonin is an endogenous amine synthesized by the enzymes tryptophan hydroxylase and decarboxylase from 5-hydroxytryptophane (5-HTP) and is metabolized by the enzyme monoamino-oxidase A to 5-hydroxyindole-3-acetic acid. 7 Serotonin has multiple cardiovascular effects, causing either blood vessel dilation through its 5-HT 1...

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Section: Discussionmentioning

confidence: 99%

Pregnant Rats Treated With a Serotonin Precursor Have Reduced Fetal Weight and Lower Plasma Volume and Kallikrein Levels

et al. 2007

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“…Both SERT and NET proteins are functionally active in the human placenta at term. Because these transporters critically regulate extracellular monoamine concentrations, they could play a role in maintaining homeostasis in amniotic fluid and fetal circulation (Prasad et al, 1994a): they clear the maternal blood of excessive amounts of catecholamines and serotonine, preventing preeclampsia (Bottalico et al, 2004). In addition, the monoamine oxidases A, which allow the intracellular degradation of monoamines after uptake from the extracellular space, are less expressed and less active in placentas from preeclamptic pregnancies (Kaaja et al, 1999;Carrasco et al, 2000;Sivasubramaniam et al, 2002).…”

Section: Solute Carrier Transportersmentioning

confidence: 99%

The Role of the Placenta in Fetal Exposure to Xenobiotics: Importance of Membrane Transporters and Human Models for Transfer Studies

Prouillac

Lecoeur²

2010

Drug Metabolism and Disposition

179

127

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ABSTRACT:The placenta is a key organ in fetal growth and development because it controls maternal-to-fetal exchanges of nutrients and hormones. It also interferes with drug delivery to the fetus by expressing active membrane transporters and xenobiotic metabolism enzymes. Developing strategies to understand the role of the placenta in drug delivery is a challenge in toxicology. Despite common physiological functions, the placentas of different species are heterogeneous in their morphology and in their expression of membrane transporters and metabolizing proteins. These characteristics raise the difficulty of obtaining a good representative model of human placental transfer. To date, different in vitro, in vivo, and ex vivo tools have been used to elucidate transport and metabolism processes in the human placenta. This study recapitulates the typical features of human placenta and then presents the placental enzymes of xenobiotic metabolism, ATP-binding cassette transporters, solute carrier transporters, and their role in fetal exposure to xenobiotics. The study also compares the characteristics of different models of human placenta, in terms of membrane localization of transporters, and the expression of xenobiotic metabolism enzymes. The use of these models for toxicological studies, in particular xenobiotic transfer, is described, and the advantages and limits of each model are summarized.

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“…Results of Ming et al [14] also indicate the placental presence of OCT1 and refute the expression of OCT2. Bottalico et al recently reported the expression of both OCT1 and OCT2 mRNAs in scattered cells of placental vessel adventitias [21]. There are no prior investigations reported in the literature concerning OCT1 and OCT2 expression in BeWo cells.…”

Section: Discussionmentioning

confidence: 99%

Low-affinity uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in BeWo cells

Rytting¹,

Bryan²,

Southard³

et al. 2007

Biochemical Pharmacology

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Understanding the mechanisms of transport processes in the placenta can improve the safety and efficacy of drug delivery during pregnancy. Functional studies of Organic Cation Transporters (OCTs) are usually carried out using radioactivity, and a fluorescent marker would add flexibility to experimental methods. As a published substrate for OCT1 and OCT2, the fluorescent compound 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) was chosen as a candidate for studying placental OCT function in BeWo cells. The expression of OCT1 and OCT2 was also investigated in BeWo cells, an established human choriocarcinoma trophoblastic cell line frequently used as an in vitro model of the rate-limiting barrier for maternal-fetal exchange of drugs and nutrients within the placenta. 4-Di-1-ASP was taken up into BeWo cells by a low-affinity, carrier-mediated process exhibiting a K m of 580 ± 110 M and V max of 97 ± 9 nmol/mg protein/30 min, and asymmetric transport was observed, with greater permeability in the apical to basolateral (maternal to fetal) direction. However, RT-PCR revealed no expression of OCT1 or OCT2 in either BeWo cells or primary cultured human cytotrophoblast cells, and OCT substrates such as TEA and choline did not inhibit the uptake of 4-Di-1-ASP. Although the uptake of this fluorescent compound in BeWo cells is not mediated by an OCT, the colocalization experiments with fluorescence microscopy and inhibition studies confirmed significant mitochondrial uptake of 4-Di-1-ASP. Transport of 4-Di-1-ASP into the nuclear region of BeWo cells was also observed, which is likely mediated by a nucleoside transporter.

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Norepinephrine Transporter (NET), Serotonin Transporter (SERT), Vesicular Monoamine Transporter (VMAT2) and Organic Cation Transporters (OCT1, 2 and EMT) in Human Placenta from Pre-eclamptic and Normotensive Pregnancies

Cited by 95 publications

References 49 publications

Pregnant Rats Treated With a Serotonin Precursor Have Reduced Fetal Weight and Lower Plasma Volume and Kallikrein Levels

Pregnant Rats Treated With a Serotonin Precursor Have Reduced Fetal Weight and Lower Plasma Volume and Kallikrein Levels

The Role of the Placenta in Fetal Exposure to Xenobiotics: Importance of Membrane Transporters and Human Models for Transfer Studies

Low-affinity uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in BeWo cells

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