(L-)tryptophan is metabolized via the kynurenine pathway into several kynurenine metabolites with distinct functions. Dysfunction of the kynurenine pathway can lead to impairments in vascular regulation, immune regulation, and tolerance. The first and rate limiting enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is highly expressed in the placenta and reduced in placentas from complicated pregnancies. IDO is essential during pregnancy, as IDO inhibition in pregnant mice resulted in fetal loss. However, the exact function of placental IDO, as well as its exact placental localization, remain controversial. This review identified that two isoforms of IDO; IDO1 and IDO2, are differently expressed between placental cells, suggesting spatial segregation. Furthermore, this review summarizes how the placental kynurenine pathway is altered in pregnancy complications, including recurrent miscarriage, preterm birth, preeclampsia, and fetal growth restriction. Importantly, we describe that these alterations do not affect maternally circulating metabolite concentrations, suggesting that the kynurenine pathway functions as a local signaling pathway. In the placenta, it is an important source of de novo placental NAD⁺ synthesis and regulates fetal tryptophan and kynurenine metabolite supply. Therefore, kynurenine pathway interventions might provide opportunities to treat pregnancy complications, and this review discusses how such treatment could affect placental function and pregnancy development.

L -tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1–dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l -tryptophan–induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations. Despite IDO1 downregulation, kynurenine pathway metabolite concentrations (measured with ultra-performance liquid chromatography-tandem mass spectrometry) were unaltered in preeclamptic versus healthy placentas. Most likely, this is due to enhanced l -tryptophan uptake, evidenced by increased l -tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts of l -tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by adding l -tryptophan in the maternal circulation, suggesting that l -tryptophan metabolites act intracellularly. Maternally applied l -tryptophan did appear in the fetal circulation, confirming placental passage of this essential amino acid. After in vitro incubation of placental arteries with IDO1-upregulating cytokines interferon-γ and tumor necrosis factor-α, l -tryptophan induced vasodilation. This vasodilation was attenuated by both IDO1 and nitric oxide (NO) synthase inhibitors. Despite IDO1 downregulation, l -tryptophan–induced relaxation was enhanced in preeclamptic versus healthy placental arteries. However, cytokine stimulation additionally upregulated the LAT ( l -type amino acid transporter) 1 in preeclamptic placental arteries only. Vasodilation to the lipophilic, transporter independent ethyl ester of l -tryptophan was reduced in preeclamptic versus healthy placental arteries, in agreement with reduced IDO1 expression. In conclusion, l -tryptophan induces IDO1- and NO-dependent relaxation in placental arteries, which is determined by l -tryptophan uptake rather than IDO1 expression. Increased l -tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.

Since the full development of the ex vivo dual perfusion model of the human placenta cotyledon, the technique has provided essential insight into how nutrients, lipids, gases, immunoglobulins, endocrine agents, pharmaceuticals, chemicals, nanoparticles, micro-organisms and parasites might traverse the maternofetal barrier. Additionally, the model has been instrumental in gaining a better understanding of the regulation of vascular tone, endocrinology and metabolism within this organ. The human placenta is unique amongst species in its anatomy and transfer modalities. This orthologous diversity therefore requires an appropriate consideration of placental transfer rates of compounds, particles and micro-organisms specific to humans. Different research centres have adapted this model with a wide variation in perfusion parameters, including in the establishment of perfusion, perfusate composition, gassing regime, cannulation method, flow rates, perfused tissue mass, and also in the application of quality control measures. The requirement to harmonise and standardise perfusion practice between centres is largely driven by the need to obtain consistency in our understanding of placental function, but also in the qualification of the model for acceptance by regulatory agencies in drug and toxicology testing. A pilot study is proposed, aiming to describe how existing inter-centre variation in perfusion methodology affects placental metabolism, protein synthesis, oxygen consumption, the materno-fetal transfer of key molecular markers, and placental structure.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor–dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

Background: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors. Methods: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole. Results: Mean maternal age was 30 years, and median gestational age was 30 ⁺³ weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P =0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio’s 0.43–0.59), while only esomeprazole inhibited placental sFlt-1 release. Conclusions: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin–angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis.