Differential Distribution of Tryptophan-Metabolites in Fetal and Maternal Circulations During Normotensive and Preeclamptic Pregnancies

Zhao, Yingjie; Zhou, Chi; Wei, Yingying; Li, Hui; Lei, Wei; Boeldt, Derek S.; Wang, Kai; Zheng, Jing

doi:10.1007/s43032-021-00759-0

Cited by 12 publications

(18 citation statements)

References 43 publications

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“…As described earlier, increased maternal tryptophan concentrations in preeclamptic compared to healthy term women are unlikely to reflect placental alterations. This might explain why the concentrations of tryptophan and kynurenine pathway metabolites did not differ between preeclamptic and healthy pregnancies at term in the maternal circulation, nor in the umbilical artery and umbilical vein [ 29 , 103 ]. However, kynurenine metabolite concentrations could still function as a biomarker, as kynurenic acid was increased in the circulation of women who later developed preeclampsia [ 104 ].…”

Section: Pathological Pregnanciesmentioning

confidence: 99%

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

Broekhuizen

Danser

Merkus

2021

IJERPH

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(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.

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Section: Pathological Pregnanciesmentioning

confidence: 99%

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

Broekhuizen

Danser

Merkus

2021

IJERPH

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“…However, the rise in the concentrations of these metabolites was not large enough to result in statistically significant different concentrations between women with PE and uncomplicated pregnancies in this study. 45 Most studies did also not identify altered tryptophan concentrations in women with PE in the third trimester of pregnancy (Zhao et al 45 : QS = 4, median (SE) = 37.0 (1.2) in PE vs 34.5 (1.3) in controls, N = 40, P ⩾ .05 ; Liu et al 46 : QS = 4, N = 38, P ⩾ .05; Jääskeläinen et al 43 : QS = 6, N = 71, P ⩾ .05). Only one study reported increased tryptophan in late-onset PE specifically (QS = 6, mean (SD): 42.8 (6.9) vs 32.7 (4.8) µmol/L, N = 33, P < .001).…”

Section: Resultsmentioning

confidence: 99%

“…2 Instead, it might originate from another (yet unknown) source, and did not seem to affect the fetal kynurenic acid concentration. 45…”

Section: Discussionmentioning

confidence: 99%

“…33,73 Preeclampsia. An elevated kynurenic acid concentration in the first trimester of pregnancy before the onset of PE, 42 and its correlation with proteinuria in women with PE 45 could either be a consequence of early PE disturbances or an actual pathophysiological factor in PE. Although tryptophan and kynurenine concentrations were not altered in women with PE, the kynurenic acid concentration was elevated.…”

Section: Maternal Pregnancy Outcomesmentioning

confidence: 99%

“…2 Instead, it might originate from another (yet unknown) source, and did not seem to affect the fetal kynurenic acid concentration. 45 Pregnancy-induced hypertension. Given the lower kynurenine concentration in women with PIH versus PE as identified through metabolomics, 48 and the similar concentration of kynurenine in PE and healthy women, it seems that women with PIH have both an increased tryptophan and a decreased kynurenine concentration.…”

Section: Maternal Pregnancy Outcomesmentioning

confidence: 99%

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The Role of the Kynurenine Pathway in the (Patho) physiology of Maternal Pregnancy and Fetal Outcomes: A Systematic Review

Zundert

Broekhuizen

Smit

et al. 2022

Int J�Tryptophan�Res

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Introduction: Tryptophan is the precursor of kynurenine pathway (KP) metabolites which regulate immune tolerance, energy metabolism, and vascular tone. Since these processes are important during pregnancy, changes in KP metabolite concentrations may play a role in the pathophysiology of pregnancy complications. We hypothesize that KP metabolites can serve as novel biomarkers and preventive therapeutic targets. This review aimed to provide more insight into associations between KP metabolite concentrations in maternal and fetal blood, and in the placenta, and adverse maternal pregnancy and fetal outcomes. Methods: A systematic search was performed on 18 February 2022 comprising all KP metabolites, and keywords related to maternal pregnancy and fetal outcomes. English-written human studies measuring KP metabolite(s) in maternal or fetal blood or in the placenta in relation to pregnancy complications, were included. Methodological quality was assessed using the ErasmusAGE quality score (QS) (range: 0-10). A meta-analysis of the mean maternal tryptophan and kynurenine concentrations in uncomplicated pregnancies was conducted. Results: Of the 6262 unique records, 37 were included (median QS = 5). Tryptophan was investigated in most studies, followed by kynurenine, predominantly in maternal blood (n = 28/37), and in the second and third trimester of pregnancy (n = 29/37). Compared to uncomplicated pregnancies, decreased tryptophan in maternal blood was associated with an increased prevalence of depression, gestational diabetes mellitus, fetal growth restriction, spontaneous abortion, and preterm birth. Elevated tryptophan was only observed in women with pregnancy-induced hypertension compared to normotensive pregnant women. In women with preeclampsia, only kynurenic acid was altered; elevated in the first trimester of pregnancy, and positively associated with proteinuria in the third trimester of pregnancy. Conclusions: KP metabolite concentrations were altered in a variety of maternal pregnancy and fetal complications. This review implies that physiological pregnancy requires a tight balance of KP metabolites, and that disturbances in either direction are associated with adverse maternal pregnancy and fetal outcomes.

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Coordinated Metabolic Responses Facilitate Cardiac Growth in Pregnancy and Exercise

Schulman-Geltzer,

Collins,

Hill

et al. 2023

Curr Heart Fail Rep

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Purpose of Review Pregnancy and exercise are systemic stressors that promote physiological growth of the heart in response to repetitive volume overload and maintenance of cardiac output. This type of remodeling is distinct from pathological hypertrophy and involves different metabolic mechanisms that facilitate growth; however, it remains unclear how metabolic changes in the heart facilitate growth and if these processes are similar in both pregnancy- and exercise-induced cardiac growth. Recent Findings The ability of the heart to metabolize a myriad of substrates balances cardiac demands for energy provision and anabolism. During pregnancy, coordination of hormonal status with cardiac reductions in glucose oxidation appears important for physiological growth. During exercise, a reduction in cardiac glucose oxidation also appears important for physiological growth, which could facilitate shuttling of glucose-derived carbons into biosynthetic pathways for growth. Understanding the metabolic underpinnings of physiological cardiac growth could provide insight to optimize cardiovascular health and prevent deleterious remodeling, such as that which occurs from postpartum cardiomyopathy and heart failure. Summary This short review highlights the metabolic mechanisms known to facilitate pregnancy-induced and exercise-induced cardiac growth, both of which require changes in cardiac glucose metabolism for the promotion of growth. In addition, we mention important similarities and differences of physiological cardiac growth in these models as well as discuss current limitations in our understanding of metabolic changes that facilitate growth.

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Differential Distribution of Tryptophan-Metabolites in Fetal and Maternal Circulations During Normotensive and Preeclamptic Pregnancies

Cited by 12 publications

References 43 publications

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

The Role of the Kynurenine Pathway in the (Patho) physiology of Maternal Pregnancy and Fetal Outcomes: A Systematic Review

Coordinated Metabolic Responses Facilitate Cardiac Growth in Pregnancy and Exercise

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