Iron nitrosyl complexes are formed from nitrite in the human placenta

Mukosera, George T.; Principe, Patricia; Mata‐Greenwood, Eugenia; Liu, Taiming; Schroeder, Hobe; Parast, Mana M.; Blood, Arlin B.

doi:10.1016/j.jbc.2022.102078

Cited by 5 publications

(14 citation statements)

References 51 publications

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“…The arteriovenous gradient of FeNO species also suggests there is dynamic production of this specific NOx species in the placenta as well as consumption by the fetus at rates that result in significant turnover of the overall FeNO pool within the circulatory transit time through the body. Gradients of various NOx species between fetus and mother, artery and vein, and plasma and blood/RBCs have been reported previously [ 63 , 64 , 65 , 66 , 67 , 68 ]. However, no consensus has been reached, in large part due to methodological concerns about the specificity of the assays for various NOx species, leading to debate over which NOx species, if any, is the prevalent bioactive metabolite of NO in the circulation [ 69 , 70 ].…”

Section: Discussionmentioning

confidence: 88%

“…This may play a significant role in the rapid increase in systemic vascular tone that occurs in the newborn within minutes after birth [ 27 ]. In addition, our recent work demonstrated that the placenta efficiently converts nitrite into heme-iron nitrosyl complexes [ 66 ], an endogenous placental NOx that may be altered in pregnancies complicated by preeclampsia [ 28 ]. Therefore, the fetal RBC FeNO effluxed from placenta at high altitude probably was HbNO ( Figure 4 D).…”

Section: Discussionmentioning

confidence: 99%

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Chronic High-Altitude Hypoxia Alters Iron and Nitric Oxide Homeostasis in Fetal and Maternal Sheep Blood and Aorta

et al. 2022

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The mammalian fetus thrives at oxygen tensions much lower than those of adults. Gestation at high altitude superimposes hypoxic stresses on the fetus resulting in increased erythropoiesis. We hypothesized that chronic hypoxia at high altitude alters the homeostasis of iron and bioactive nitric oxide metabolites (NOx) in gestation. To test for this, electron paramagnetic resonance was used to provide unique measurements of iron, metalloproteins, and free radicals in the blood and aorta of fetal and maternal sheep from either high or low altitudes (3801 or 300 m). Using ozone-based chemiluminescence with selectivity for various NOx species, we determined the NOx levels in these samples immediately after collection. These experiments demonstrated a systemic redistribution of iron in high altitude fetuses as manifested by a decrease in both chelatable and total iron in the aorta and an increase in non-transferrin bound iron and total iron in plasma. Likewise, high altitude altered the redox status diversely in fetal blood and aorta. This study also found significant increases in blood and aortic tissue NOx in fetuses and mothers at high altitude. In addition, gradients in NOx concentrations observed between fetus and mother, umbilical artery and vein, and plasma and RBCs demonstrated complex dynamic homeostasis of NOx among these circulatory compartments, such as placental generation and efflux as well as fetal consumption of iron-nitrosyls in RBCs, probably HbNO. In conclusion, these results may suggest the utilization of iron from non-hematopoietic tissues iron for erythropoiesis in the fetus and increased NO bioavailability in response to chronic hypoxic stress at high altitude during gestation.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Chronic High-Altitude Hypoxia Alters Iron and Nitric Oxide Homeostasis in Fetal and Maternal Sheep Blood and Aorta

et al. 2022

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“…As a result, over the course of the 24 h treatment period with 500 μM DETA, an accumulation of as much as 250 μM nitrite would be expected. While nitrate is thought to be inert in the placenta, we have recently reported that nitrite can be converted into iron nitrosyls (FeNOs) [ 18 ], raising the possibility that the nitrite accumulating in the culture media over the course of the 24 h experiment may confound our goal of assessing the effects of NO itself. To control for this possibility, a control group that received 250 μM nitrite was included in addition to the true negative control group, which received 250 μM nitrate.…”

Section: Resultsmentioning

confidence: 99%

“…Iron nitrosyl complexes (FeNOs) have the potential to act as either sinks or stores of NO, thus modulating the amount of both free NO and iron within the cell. While recent discoveries indicate FeNOs play a physiological role in the placenta [ 17 , 18 , 20 ], the extent to which FeNO formation might influence intracellular iron homeostasis in the placenta is unknown. In this study, we showed that exposure of syncytiotrophoblast cells and villous placental explants to NO at concentrations below the threshold of toxicity results in FeNO formation.…”

Section: Discussionmentioning

confidence: 99%

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Nitric Oxide Affects Heme Oxygenase-1, Hepcidin, and Transferrin Receptor Expression in the Placenta

Principe

Mukosera

Gray-Hutto

et al. 2023

IJMS

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Nitric oxide (NO) is a gasotransmitter that avidly binds both free and heme-bound iron, forming relatively stable iron nitrosyl compounds (FeNOs). We have previously demonstrated that FeNOs are present in the human placenta and are elevated in preeclampsia and intrauterine growth restriction. The ability of NO to sequester iron raises the possibility of the NO-mediated disruption of iron homeostasis in the placenta. In this work, we tested whether exposure of placental syncytiotrophoblasts or villous tissue explants to sub-cytotoxic concentrations of NO would elicit the formation of FeNOs. Furthermore, we measured changes in the mRNA and protein expression levels of key iron regulatory genes in response to NO exposure. Ozone-based chemiluminescence was used to measure concentrations of NO and its metabolites. Our results showed a significant increase in FeNO levels in placental cells and explants treated with NO (p < 0.0001). The mRNA and protein levels of HO-1 were significantly increased in both cultured syncytiotrophoblasts and villous tissue explants (p < 0.01), and the mRNA levels of hepcidin and transferrin receptor were significantly increased in culture syncytiotrophoblasts and villous tissue explants, respectively, (p < 0.01), while no changes were seen in the expression levels of divalent metal transporter-1 or ferroportin. These results suggest a potential role for NO in iron homeostasis in the human placenta and could be relevant for disorders of pregnancy such as fetal growth restriction and preeclampsia.

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Specific dilation pattern in placental circulation and the NO/sGC role in preeclampsia placental vessels

Tang

Zhang

et al. 2023

Front. Endocrinol.

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ObjectiveEndothelial functions in controlling blood flow in placental circulation are still unclear. The present study compares vascular dilations between placental circulation and other vessels, as well as between normal and preeclampsia placental vessels.MethodsPlacental, umbilical, and other vessels (cerebral and mesenteric arteries) were collected from humans, sheep, and rats. Vasodilation was tested by JZ101 and DMT. Q-PCR, Western blot, and Elisa were used for molecular experiments.ResultsEndothelium-dependent/derived vasodilators, including acetylcholine, bradykinin, prostacyclin, and histamine, mediated no or minimal dilation in placental circulation, which was different from that in other vessels in sheep and rats. There were lower mRNA expressions of muscarinic receptors, histamine receptors, bradykinin receptor 2, endothelial nitric oxide synthesis (eNOS), and less nitric oxide (NO) in human umbilical vessels when compared with placental vessels. Exogenous NO donors (sodium nitroprusside, SNP) and soluble guanylate cyclase (sGC) activators (Bay41-2272) decreased the baseline of vessel tone in placental circulation in humans, sheep, and rats, but not in other arteries. The sGC inhibitor ODQ suppressed the reduced baseline caused by the SNP. The decreased baseline by SNP or Bay41-2272 was higher in placental vessels than in umbilical vessels, suggesting that the role of NO/sGC is more important in the placenta. NO concentrations in preeclampsia placental vessels were lower than those in control, while no significant change was found in umbilical plasma between the two groups. eNOS expression was similar between normal and preeclampsia placental vessels, but phosphorylated eNOS levels were significantly lower in preeclampsia. Following serotonin, SNP or Bay41-2272-mediated dilations were weaker in preeclampsia placental vessels. The decreased amplitude of SNP- or Bay41-2272 at baseline was smaller in preeclampsia. The decreased amplitudes of ODQ + SNP were comparable between the two groups. Despite higher beta sGC expression, sGC activity in the preeclampsia placenta was lower.ConclusionThis study demonstrated that receptor-mediated endothelium-dependent dilation in placental circulation was significantly weaker than other vessels in various species. The results, showed firstly, that exogenous NO played a role in regulating the baseline tone of placental circulation via sGC. Lower NO production and decreased NO/sGC could be one of the reasons for preeclampsia. The findings contribute to understanding specific features of placental circulation and provide information about preeclampsia in placental vessels.

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Iron nitrosyl complexes are formed from nitrite in the human placenta

Cited by 5 publications

References 51 publications

Chronic High-Altitude Hypoxia Alters Iron and Nitric Oxide Homeostasis in Fetal and Maternal Sheep Blood and Aorta

Chronic High-Altitude Hypoxia Alters Iron and Nitric Oxide Homeostasis in Fetal and Maternal Sheep Blood and Aorta

Nitric Oxide Affects Heme Oxygenase-1, Hepcidin, and Transferrin Receptor Expression in the Placenta

Specific dilation pattern in placental circulation and the NO/sGC role in preeclampsia placental vessels

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