Journal articles: 'Placental hypoxia/reoxygenation'

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BURTON, GRAHAM J., and TAI-HO HUNG. "HYPOXIA-REOXYGENATION; A POTENTIAL SOURCE OF PLACENTAL OXIDATIVE STRESS IN NORMAL PREGNANCY AND PREECLAMPSIA." Fetal and Maternal Medicine Review 14, no. 2 (May 2003): 97–117. http://dx.doi.org/10.1017/s0965539503001049.

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It is now over half a century since Arthur Hertig first reported vascular pathology in the uterine arteries supplying the placenta in women suffering from preeclampsia. His pioneering histological studies have been validated and extended by many others, leading to the general concept that placental perfusion is compromised in these patients. More recent Doppler ultrasound studies have confirmed reduced intervillous blood flow in vivo, and so gradually a consensus has emerged that the placental lesions associated with preeclampsia arise from a state of chronic hypoxia. Whilst hypoxia may undoubtedly play a significant role in the generation of placental pathology, there is considerable evidence that another feature of the intervillous circulation, namely the constancy of the blood flow, may be a more important factor. In this review we propose that hypoxia-reoxygenation, secondary to intermittent perfusion of the intervillous space, is a more physiological approach to take to understanding the pathophysiology of both normal pregnancies, and those complicated by preeclampsia. We further propose that chronic reduction in placental perfusion alone may lead to fetal growth restriction, and that if the two phenomena are superimposed then preeclampsia with growth restriction will result.

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Jakoubek, Vít, Jana Bíbová, Jan Herget, and Václav Hampl. "Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 4 (April 2008): H1638—H1644. http://dx.doi.org/10.1152/ajpheart.01120.2007.

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An increase in fetoplacental vascular resistance caused by hypoxia is considered one of the key factors of placental hypoperfusion and fetal undernutrition leading to intrauterine growth restriction (IUGR), one of the serious problems in current neonatology. However, although acute hypoxia has been shown to cause fetoplacental vasoconstriction, the effects of more sustained hypoxic exposure are unknown. This study was designed to test the hypothesis that chronic hypoxia elicits elevations in fetoplacental resistance, that this effect is not completely reversible by acute reoxygenation, and that it is accompanied by increased acute vasoconstrictor reactivity of the fetoplacental vasculature. We measured fetoplacental vascular resistance as well as acute vasoconstrictor reactivity in isolated perfused placentae from rats exposed to hypoxia (10% O2) during the last week of a 3-wk pregnancy. We found that chronic hypoxia shifted the relationship between perfusion pressure and flow rate toward higher pressure values (by ∼20%). This increased vascular resistance was refractory to a high dose of sodium nitroprusside, implying the involvement of other factors than increased vascular tone. Chronic hypoxia also increased vasoconstrictor responses to angiotensin II (by ∼75%) and to acute hypoxic challenges (by >150%). We conclude that chronic prenatal hypoxia causes a sustained elevation of fetoplacental vascular resistance and vasoconstrictor reactivity that are likely to produce placental hypoperfusion and fetal undernutrition in vivo.

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Cheng, Shibin, Zheping Huang, Sayani Banerjee, Sukanta Jash, Joel N. Buxbaum, and Surendra Sharma. "Evidence From Human Placenta, Endoplasmic Reticulum–Stressed Trophoblasts, and Transgenic Mice Links Transthyretin Proteinopathy to Preeclampsia." Hypertension 79, no. 8 (August 2022): 1738–54. http://dx.doi.org/10.1161/hypertensionaha.121.18916.

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Background: We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia and identified several aggregated proteins in the circulation of preeclampsia patients, the most prominent of which is the serum protein TTR (transthyretin). However, the mechanisms that underlie protein aggregation remain poorly addressed. Methods: We examined TTR aggregates in hypoxia/reoxygenation-exposed primary human trophoblasts (PHTs) and the preeclampsia placenta using complementary approaches, including a novel protein aggregate detection assay. Mechanistic analysis was performed in hypoxia/reoxygenation-exposed PHTs and Ttr transgenic mice overexpressing transgene-encoded wild-type human TTR or Ttr −/− mice. High-resolution ultrasound analysis was used to measure placental blood flow in pregnant mice. Results: TTR aggregation was inducible in PHTs and the TCL-1 trophoblast cell line by endoplasmic reticulum stress inducers or autophagy-lysosomal disruptors. PHTs exposed to hypoxia/reoxygenation showed increased intracellular BiP (binding immunoglobulin protein), phosphorylated IRE1α (inositol-requiring enzyme-1α), PDI (protein disulfide isomerase), and Ero-1, all markers of the unfolded protein response, and the apoptosis mediator caspase-3. Blockade of IRE1α inhibited hypoxia/reoxygenation-induced upregulation of Ero-1 in PHTs. Excessive unfolded protein response activation was observed in the early-onset preeclampsia placenta. Importantly, pregnant human TTR mice displayed aggregated TTR in the junctional zone of the placenta and severe preeclampsia-like features. High-resolution ultrasound analysis revealed low blood flow in uterine and umbilical arteries in human TTR mice compared with control mice. However, Ttr −/− mice did not show any pregnancy-associated abnormalities. Conclusions: These observations in the preeclampsia placenta, cultured trophoblasts, and Ttr transgenic mice indicate that TTR aggregation is an important causal contributor to preeclampsia pathophysiology.

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Nevo, Ori, Nima Soleymanlou, Yuan Wu, Jing Xu, John Kingdom, Ariel Many, Stacy Zamudio, and Isabella Caniggia. "Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 4 (October 2006): R1085—R1093. http://dx.doi.org/10.1152/ajpregu.00794.2005.

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Elevated expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) in preeclampsia plays a major role in the pathogenesis of this serious disorder of human pregnancy. Although reduced placental oxygenation is thought to be involved in the pathogenesis of preeclampsia, it is unclear how oxygen regulates placental sFlt-1 expression. The aims herein were to investigate sFlt-1 expression in in vivo and in vitro physiological and pathological models of human placental hypoxia and to understand the role of hypoxia inducible factor-1 (HIF-1) in regulating the expression of this molecule. sFlt-1 expression in placental villi was significantly increased under physiological low oxygen conditions in early first-trimester and in high-altitude placentae, as well as in pathological low oxygen conditions, such as preeclampsia. In high-altitude and in preeclamptic tissue, sFlt-1 localized within villi to perivascular regions, the syncytiotrophoblast layer, and syncytial knots. In first-trimester villous explants, low oxygen, but not hypoxia-reoxygenation (HR), increased sFlt-1 expression. Moreover, exposure of villous explants to dimethyloxalyl-glycin, a pharmacological inhibitor of prolyl-hydroxylases, which mimics hypoxia by increasing HIF-1α stability, increased sFlt-1 expression. Conversely, HIF-1α knockdown using antisense oligonucleotides, decreased sFlt-1 expression. In conclusion, placental sFlt-1 expression is increased by both physiologically and pathologically low levels of oxygen. This oxygen-induced effect is mediated via the transcription factor HIF-1. Low oxygen levels, as opposed to intermittent oxygen tension (HR) changes, play an important role in regulating sFlt-1 expression in the developing human placenta and hence may contribute to the development of preeclampsia.

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Fuenzalida, Barbara, Sampada Kallol, Jonas Zaugg, Martin Mueller, Hiten D. Mistry, Jaime Gutierrez, Andrea Leiva, and Christiane Albrecht. "Primary Human Trophoblasts Mimic the Preeclampsia Phenotype after Acute Hypoxia–Reoxygenation Insult." Cells 11, no. 12 (June 11, 2022): 1898. http://dx.doi.org/10.3390/cells11121898.

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Preeclampsia (PE) is a pregnancy-specific disorder that affects 3 to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality. Nevertheless, how these events occur remains unclear. We hypothesized that the induction of hypoxic conditions in vitro in primary human trophoblast cells would mimic several characteristics of PE found in vivo. We applied and characterized a model of primary cytotrophoblasts isolated from healthy pregnancies that were placed under different oxygen concentrations: ambient O2 (5% pCO2, 21%pO2, 24 h, termed “normoxia”), low O2 concentration (5% pCO2, 1.5% pO2, 24 h, termed “hypoxia”), or “hypoxia/reoxygenation” (H/R: 6 h intervals of normoxia and hypoxia for 24 h). Various established preeclamptic markers were assessed in this cell model and compared to placental tissues obtained from PE pregnancies. Seventeen PE markers were analyzed by qPCR, and the protein secretion of soluble fms-like tyrosine kinase 1 (sFlT-1) and the placenta growth factor (PlGF) was determined by ELISA. Thirteen of seventeen genes associated with angiogenesis, the renin–angiotensin system, oxidative stress, endoplasmic reticulum stress, and the inflammasome complex were susceptible to H/R and hypoxia, mimicking the expression pattern of PE tissue. In cell culture supernatants, the secretion of sFlT-1 was increased in hypoxia, while PlGF release was significantly reduced in H/R and hypoxia. In the supernatants of our cell models, the sFlT-1/PlGF ratio in hypoxia and H/R was higher than 38, which is a strong indicator for PE in clinical practice. These results suggest that our cellular models reflect important pathological processes occurring in PE and are therefore suitable as PE in vitro models.

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Cheng, Shibin, Zheping Huang, Sukanta Jash, Kathleen Wu, Shigeru Saito, Akitoshi Nakashima, and Surendra Sharma. "Hypoxia-Reoxygenation Impairs Autophagy-Lysosomal Machinery in Primary Human Trophoblasts Mimicking Placental Pathology of Early-Onset Preeclampsia." International Journal of Molecular Sciences 23, no. 10 (May 18, 2022): 5644. http://dx.doi.org/10.3390/ijms23105644.

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We have previously described that placental activation of autophagy is a central feature of normal pregnancy, whereas autophagy is impaired in preeclampsia (PE). Here, we show that hypoxia–reoxygenation (H/R) treatment dysregulates key molecules that maintain autophagy–lysosomal flux in primary human trophoblasts (PHTs). Ultrastructural analysis using transmission electron microscopy reveals a significant reduction in autophagosomes and autolysosomes in H/R-exposed PHTs. H/R-induced accumulation of protein aggregates follows a similar pattern that occurs in PHTs treated with a lysosomal disruptor, chloroquine. Importantly, the placenta from early-onset PE deliveries exhibits the same features as seen in H/R-treated PHTs. Taken together, our results indicate that H/R disrupts autophagic machinery in PHTs and that impaired autophagy in the placenta from early-onset PE deliveries mimics the events in H/R-treated PHTs. Notably, assessment of key regulators at each stage of autophagic processes, especially lysosomal integrity, and verification of autophagic ultrastructure are essential for an accurate evaluation of autophagy activity in human trophoblasts and placental tissue from PE deliveries.

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Beharier, Ofer, Vladimir A. Tyurin, Julie P. Goff, Jennifer Guerrero-Santoro, Kazuhiro Kajiwara, Tianjiao Chu, Yulia Y. Tyurina, et al. "PLA2G6 guards placental trophoblasts against ferroptotic injury." Proceedings of the National Academy of Sciences 117, no. 44 (October 21, 2020): 27319–28. http://dx.doi.org/10.1073/pnas.2009201117.

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The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specific manner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies.

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Yung, Hong Wa, Francesca Colleoni, Emilie Dommett, Tereza Cindrova-Davies, John Kingdom, Andrew J. Murray, and Graham J. Burton. "Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia." Proceedings of the National Academy of Sciences 116, no. 36 (August 22, 2019): 18109–18. http://dx.doi.org/10.1073/pnas.1907548116.

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Preeclampsia (PE) is a dangerous complication of pregnancy, especially when it presents at <34 wk of gestation (PE < 34 wk). It is a major cause of maternal and fetal morbidity and mortality and also increases the risk of cardiometabolic diseases in later life for both mother and offspring. Placental oxidative stress induced by defective placentation sits at the epicenter of the pathophysiology. The placenta is susceptible to activation of the unfolded protein response (UPR), and we hypothesized this may affect mitochondrial function. We first examined mitochondrial respiration before investigating evidence of mitochondrial UPR (UPRmt) in placentas of PE < 34 wk patients. Reduced placental oxidative phosphorylation (OXPHOS) capacity measured in situ was observed despite no change in protein or mRNA levels of electron transport chain complexes. These results were fully recapitulated by subjecting trophoblast cells to repetitive hypoxia–reoxygenation and were associated with activation of a noncanonical UPRmt pathway; the quality-control protease CLPP, central to UPRmt signal transduction, was reduced, while the cochaperone, TID1, was increased. Transcriptional factor ATF5, which regulates expression of key UPRmt genes including HSP60 and GRP75, showed no nuclear translocation. Induction of the UPRmt with methacycline reduced OXPHOS capacity, while silencing CLPP was sufficient to reduce OXPHOS capacity, membrane potential, and promoted mitochondrial fission. CLPP was negatively regulated by the PERK-eIF2α arm of the endoplasmic reticulum UPR pathway, independent of ATF4. Similar changes in the UPRmt pathway were observed in placentas from PE < 34 wk patients. Our results identify UPRmt as a therapeutic target for restoration of placental function in early-onset preeclampsia.

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Hung, Tai-Ho, and Graham J. Burton. "Hypoxia and Reoxygenation: a Possible Mechanism for Placental Oxidative Stress in Preeclampsia." Taiwanese Journal of Obstetrics and Gynecology 45, no. 3 (September 2006): 189–200. http://dx.doi.org/10.1016/s1028-4559(09)60224-2.

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Sagrillo-Fagundes, Lucas, Eugênia M. Assunção Salustiano, Rodrigo Ruano, Regina P. Markus, and Cathy Vaillancourt. "Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia/reoxygenation." Journal of Pineal Research 65, no. 4 (September 3, 2018): e12520. http://dx.doi.org/10.1111/jpi.12520.

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Ogunleye, Oluseyi, Bertha Campo, Diana Herrera, Emiel D. Post Uiterweer, and Kirk P. Conrad. "Relaxin confers cytotrophoblast protection from hypoxia-reoxygenation injury through the phosphatidylinositol 3-kinase-Akt/protein kinase B cell survival pathway." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 312, no. 4 (April 1, 2017): R559—R568. http://dx.doi.org/10.1152/ajpregu.00306.2016.

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Preeclampsia is a hypertensive syndrome that manifests after 20 wk of gestation. Contemporary understanding of the maternal-fetal interface in preeclampsia suggests a major role for placental oxidative stress resulting from ischemia-reperfusion injury. We hypothesized that the pregnancy hormone relaxin would reduce cytotrophoblast apoptosis and necrosis (aponecrosis) and, hence, the export of placental debris into the maternal circulation. If so, then relaxin might be employed as a therapeutic intervention to diminish the activation of the maternal systemic inflammatory response central to the development of clinical disease. HTR-8/SVneo cells, a model for first trimester extravillous trophoblast, were subjected to serum deprivation and hypoxia or hypoxia-reoxygenation. The cells were treated with recombinant human relaxin or vehicle and apoptosis and/or necrosis evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), CellEvent Caspase-3/7 and SYTOX AADvanced kit, and propidium iodide staining as determined by fluorescence microscopy or flow cytometry. To interrogate mechanisms of relaxin cytoprotection, HTR-8/SVneo cells were pretreated with pharmacological inhibitors of PI3-kinase LY294004, Akt/PKB MK-2206, or DMSO vehicle. HTR-8/SVneo cell identity was first confirmed by RT-PCR. The cells expressed placental alkaline phosphatase, aromatase, and human leukocyte antigen G. In addition, the cells expressed the relaxin receptor RXFP1 as well as H1 and H2 relaxins. Serum deprivation and hypoxia increased apoptotic cell death in HTR-8/SVneo cells, which was significantly ameliorated by concurrent treatment with relaxin. Serum deprivation and hypoxia-reoxygenation increased necrotic cell death in HTR-8/SVneo cells, which was also significantly rescued by concurrent treatment with relaxin. Pretreatment with LY294002 or MK-2206, to inhibit the phosphatidylinositol 3-kinase-Akt/protein kinase B cell survival pathway, significantly blunted the cytoprotective effect of relaxin. We demonstrated trophoblast cytoprotection by intervention with supraphysiological concentrations of relaxin, a process in part mediated through the PI3-kinase-Akt/PKB cell survival pathway. These results provide further rationale for clinical investigation of relaxin as a potential therapeutic in preeclampsia.

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Michelassi, Stefano. "Preeclampsia: Parte 1°: clinica, anatomia patologica e fisiologia." Giornale di Clinica Nefrologica e Dialisi 31, no. 1 (May 8, 2019): 4–11. http://dx.doi.org/10.33393/gcnd.2019.505.

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Preeclampsia is a pregnancy-specific disorder usually characterised by new-onset hypertension and proteinuria after the 20th week of gestation. Preeclampsia is a systemic disease with multiorgan involvement and is associated to a high risk of maternal and fetal morbidity and mortality. To date, its pathogenesis is not completely understood, but placental hypoxia or hypoxia/reoxygenation may be the basic condition leading to systemic inflammation and endothelial dysfunction, which in turn induce all the clinical manifestations of the disorder. Delivery is the only curative treatment. In the management of preeclampsia two kinds of risks need to be considered: the maternal risks, due to continued pregnancy, and the fetal risks, associated with induced preterm delivery.

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Ong, P., and G. J. Burton. "The effects of hypoxia and reoxygenation on barrier thickness of placental villi maintained in organ culture." Placenta 10, no. 5 (September 1989): 462–63. http://dx.doi.org/10.1016/0143-4004(89)90073-8.

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Almendros, Isaac, Paula Martínez-Ros, Nuria Farré, Mónica Rubio-Zaragoza, Marta Torres, Álvaro J. Gutiérrez-Bautista, José M. Carrillo-Poveda, et al. "Placental oxygen transfer reduces hypoxia-reoxygenation swings in fetal blood in a sheep model of gestational sleep apnea." Journal of Applied Physiology 127, no. 3 (September 1, 2019): 745–52. http://dx.doi.org/10.1152/japplphysiol.00303.2019.

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Obstructive sleep apnea (OSA), characterized by events of hypoxia-reoxygenation, is highly prevalent in pregnancy, negatively affecting the gestation process and particularly the fetus. Whether the consequences of OSA for the fetus and offspring are mainly caused by systemic alterations in the mother or by a direct effect of intermittent hypoxia in the fetus is unknown. In fact, how apnea-induced hypoxemic swings in OSA are transmitted across the placenta remains to be investigated. The aim of this study was to test the hypothesis, based on a theoretical background on the damping effect of oxygen transfer in the placenta, that oxygen partial pressure (Po2) swings resulting from obstructive apneas mimicking OSA are mitigated in the fetal circulation. To this end, four anesthetized ewes close to term pregnancy were subjected to obstructive apneas consisting of 25-s airway obstructions. Real-time Po2 was measured in the maternal carotid artery and in the umbilical vein with fast-response fiber-optic oxygen sensors. The amplitudes of Po2 swings in the umbilical vein were considerably smaller [3.1 ± 1.0 vs. 21.0 ± 6.1 mmHg (mean ± SE); P < 0.05]. Corresponding estimated swings in fetal and maternal oxyhemoglobin saturation tracked Po2 swings. This study provides novel insights into fetal oxygenation in a model of gestational OSA and highlights the importance of further understanding the impact of sleep-disordered breathing on fetal and offspring development. NEW & NOTEWORTHY This study in an airway obstruction sheep model of gestational sleep apnea provides novel data on how swings in oxygen partial pressure (Po2) translate from maternal to fetal blood. Real-time simultaneous measurement of Po2 in maternal artery and in umbilical vein shows that placenta transfer attenuates the magnitude of oxygenation swings. These data prompt further investigation of the extent to which maternal apneas could induce similar direct oxidative stress in fetal and maternal tissues.

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Thamotharan, Shanthie, David Stout, Bo-Chul Shin, and Sherin U. Devaskar. "Temporal and spatial distribution of murine placental and brain GLUT3-luciferase transgene as a readout of in vivo transcription." American Journal of Physiology-Endocrinology and Metabolism 304, no. 3 (February 1, 2013): E254—E266. http://dx.doi.org/10.1152/ajpendo.00214.2012.

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To investigate in vivo transcription of the facilitative glucose transporter isoform-GLUT3 gene, we created GLUT3-firefly luciferase transgenic mouse lines that demonstrate tissue-specific [adult: brain > testis ≥ skeletal muscle > placenta; postnatal (PN): skeletal muscle > brain = skin], temporal, and spatial distribution of the reporter gene/enzyme activity that is unique from endogenous GLUT3 mRNA/protein. In this mouse model, luciferase expression/activity serving as a readout of in vivo transcription peaked at 12 days gestation along with proliferating cell nuclear antigen (cell replication) in placenta and embryonic brain preceding peak GLUT3 protein expression at 18–19 days gestation. In contrast, a postnatal increase in brain luciferase mRNA peaked with endogenous GLUT3 mRNA, but after that of NeuroD6 protein (neurogenesis) at PN7. Luciferase activity paralleled GLUT3 protein expression with Na+-K+-ATPase (membrane expansion) and synaptophysin (synaptogenesis) proteins, peaking at PN14 and lasting until 60 days in the adult. Thus GLUT3 transcription in placenta and embryonic brain coincided with cell proliferation and in postnatal brain with synaptogenesis. Longitudinal noninvasive bioluminescence (BLI) monitoring of in vivo brain GLUT3 transcription reflected cross-sectional ex vivo brain luciferase activity only between PN7 and PN21. Hypoxia/reoxygenation at PN7 revealed transcriptional increase in brain GLUT3 expression reflected by in vivo BLI and ex vivo luciferase activity. These observations collectively support a temporal contribution by transcription toward ensuring adequate tissue-specific, developmental (placenta and embryonic brain), and postnatal hypoxic brain GLUT3 expression.

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Almendros, I., P. Martinez-Ros, N. Farre, M. Rubio-Zaragoza, M. Torres, A. Gutierrez-Bautista, J. M. Carrillo-Poveda, et al. "Placental oxygen transfer reduces hypoxia/reoxygenation swings in fetal blood in a sheep model of gestational sleep apnea." Sleep Medicine 64 (December 2019): S110. http://dx.doi.org/10.1016/j.sleep.2019.11.302.

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Hung, Tai-Ho, D. Stephen Charnock-Jones, Jeremy N. Skepper, and Graham J. Burton. "Secretion of Tumor Necrosis Factor-α from Human Placental Tissues Induced by Hypoxia-Reoxygenation Causes Endothelial Cell Activation in Vitro." American Journal of Pathology 164, no. 3 (March 2004): 1049–61. http://dx.doi.org/10.1016/s0002-9440(10)63192-6.

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Kurlak, Lesia O., Hiten D. Mistry, Tereza Cindrova-Davies, Graham J. Burton, and Fiona Broughton Pipkin. "Human placental renin-angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia-reoxygenation insult." Journal of Physiology 594, no. 5 (January 19, 2016): 1327–40. http://dx.doi.org/10.1113/jp271045.

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Gusar, Vladislava, Angelika Timofeeva, Vitaliy Chagovets, Nataliya Kan, Oksana Vasilchenko, Kseniya Prozorovskaya, Tatyana Ivanets, and Gennadiy Sukhikh. "Preeclampsia: The Interplay between Oxygen-Sensitive miRNAs and Erythropoietin." Journal of Clinical Medicine 9, no. 2 (February 20, 2020): 574. http://dx.doi.org/10.3390/jcm9020574.

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Changes in the oxygen partial pressure caused by a violation of uteroplacental perfusion are considered a powerful inducer of a cascade of reactions leading to the clinical manifestation of preeclampsia (PE). At the same time, the induction of oxygen-dependent molecule expression, in particular, miRNA and erythropoietin, is modulated. Therefore, the focus of our study was aimed at estimating the miRNA expression profile of placental tissue and blood plasma in pregnant women with preeclampsia using deep sequencing and quantitative RT-PCR, as well as determining the concentration of erythropoietin. The expression of miR-27b-3p, miR-92b-3p, miR-125b-5p, miR-181a-5p, and miR-186-5p, as regulated by hypoxia/reoxygenation, was significantly increased in blood plasma during early-onset preeclampsia. The possibility of detecting early PE according to the logistic regression model (miR-92b-3p, miR-125b-5p, and miR-181a-5p (AUC = 0.91)) was evaluated. Furthermore, the erythropoietin level, which is regulated by miR-125b-5p, was significantly increased. According to PANTHER14.1, the participation of these miRNAs in the regulation of pathways, such as the hypoxia’s response via HIF activation, oxidative stress response, angiogenesis, and the VEGF signaling pathway, were determined.

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Ma, Ruixia, Zhijiang Liang, Xiaomei Shi, Linli Xu, Xiaowei Li, Jinhua Wu, Lina Zhao, and Guocheng Liu. "Exosomal miR-486-5p derived from human placental microvascular endothelial cells regulates proliferation and invasion of trophoblasts via targeting IGF1." Human Cell 34, no. 5 (May 11, 2021): 1310–23. http://dx.doi.org/10.1007/s13577-021-00543-x.

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AbstractPreeclampsia (PE) is a serious complication of pregnancy. Exosomes are known to be upregulated in PE. In this study, we sought to investigate the effect of miR-486-5p from human placental microvascular endothelial cells, on the function of trophoblast cells. To investigate the function of human placental microvascular endothelial cell (HPVEC)-derived exosomes on trophoblast cells, HPVECs were treated with hypoxia/reoxygenation (H/R). The separation efficiency of exosomes was determined by transmission electron microscopy, nanosight and Western blot. Cell Counting Kit-8, EdU staining, wound-healing, and transwell assay were performed to detect the effect of exosomally transferred miR-486-5p inhibitor on proliferation, migration and invasion of trophoblast cells. MiRDB and dual-luciferase report assay were used to find the target of miR-486-5p. Our data revealed that miR-486-5p was significantly upregulated in H/R-treated HPVEC-Exo, and miR-486-5p was enriched in HPVEC-Exo. miR-486-5p inhibitor carried by HPVEC-Exo significantly inhibited the proliferation, migration and invasion of trophoblast cells. Insulin-like growth factor 1 (IGF1) was found to be the target of miR-486-5p, and IGF1 overexpression notably reversed the effect of miR-486-5p inhibitor from HPVEC-Exo on trophoblast cell function. In summary, H/R-treated HPVEC-derived exosomally expressing miR-486-5p inhibitor significantly inhibited the proliferation, migration and invasion of trophoblast cells via downregulation of IGF1. The findings from the present study may be useful in the development of treatments for PE.

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Quan, Dandan, Li Li, and Manzhen Zuo. "Efficacy of Low Molecular Heparin on Preeclampsia by Inhibiting Apoptosis of Trophoblasts via the p38MAPK Signaling Pathway." Computational and Mathematical Methods in Medicine 2021 (August 2, 2021): 1–7. http://dx.doi.org/10.1155/2021/3337514.

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Objective. To explore the efficacy of low molecular heparin on preeclampsia by inhibiting apoptosis of trophoblasts via the p38MAPK signaling pathway. Methods. A preeclampsia rat model was established, and the effects of low molecular heparin on preeclampsia via the p38MAPK signaling pathway were analyzed based on intervention of the rats with different combinations of low molecular heparin and p38MAPK signaling pathway activator. Furthermore, a hypoxia/reoxygenation model of trophoblasts in vitro was established to explore the effects of low molecular heparin on trophoblasts via the p38MAPK signaling pathway. Results. After treatment with low molecular heparin, pregnant rats in the heparin group showed significantly decreased blood pressure, 24 h proteinuria, and p38MAPK protein levels in placenta tissues and decreased apoptosis rate of placenta tissue cells (all P < 0.05 ) and showed more fetal rats and lowered weight of them (both P < 0.05 ) but showed no significant change in the weight of placenta (all P > 0.05 ). Pregnant rats treated with low molecular heparin and p38MAPK activator showed significantly higher blood pressure, 24 h proteinuria, and p38MAPK protein levels in placenta tissues and apoptosis rate of placenta tissue cells than those of pregnant rats in the heparin group (all P < 0.05 ) and also showed less fetal rats and lighter fetal rats than those in the heparin group (both P < 0.05 ) but showed no difference with them in the weight of placenta ( P > 0.05 ). Further analysis revealed that low molecular heparin could protect the survival and migration of trophoblasts under hypoxia/reoxygenation conditions and reduce apoptosis of them (all P < 0.05 ). Conclusion. Low molecular heparin can alleviate preeclampsia by inhibiting the p38MAPK signaling pathway and can inhibit apoptosis of trophoblasts and promote proliferation and migration of them.

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Wood, Charles E., and Maureen Keller-Wood. "Current paradigms and new perspectives on fetal hypoxia: implications for fetal brain development in late gestation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 317, no. 1 (July 1, 2019): R1—R13. http://dx.doi.org/10.1152/ajpregu.00008.2019.

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The availability of oxygen to the fetus is limited by the route taken by oxygen from the atmosphere to fetal tissues, aided or diminished by pregnancy-associated changes in maternal physiology and, ultimately, a function of atmospheric pressure and composition of the mother’s inspired gas. Much of our understanding of the fetal physiological response to hypoxia comes from experiments designed to elucidate the cardiovascular and endocrine responses to transient hypoxia. Complementing this work is equally impactful research into the origins of intrauterine growth restriction in which animal models designed to restrict the transfer of oxygen from the maternal to the fetal circulation were used. A common assumption has been that outcomes measured after a period of hypoxia are related to cellular deprivation of oxygen and reoxygenation: an assumption based on a focus on what we can see “under the streetlights.” Recent studies demonstrate that availability of oxygen may not tell the whole story. Transient hypoxia in the fetal sheep stimulates transcriptomics responses that mirror inflammation. This response is accompanied by the appearance of bacteria in the fetal brain and other tissues, likely resulting from a hypoxia-stimulated release of bacteria from the placenta. The appearance of bacteria in the fetus after transient hypoxia complements the recent discovery of bacterial DNA in the normal human placenta and in the tissues of fetal sheep. An understanding of the mechanism of the physiological, cellular, and molecular responses to hypoxia requires an appreciation of stimuli other than cellular oxygen deprivation: stimuli that we would have never known about without looking “between the streetlights,” illuminating direct responses to the manipulated variables.

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Belkacemi, Louiza, Shannon A. Bainbridge, Michelle A. Dickinson, Graeme N. Smith, and Charles H. Graham. "Glyceryl Trinitrate Inhibits Hypoxia/Reoxygenation-Induced Apoptosis in the Syncytiotrophoblast of the Human Placenta." American Journal of Pathology 170, no. 3 (March 2007): 909–20. http://dx.doi.org/10.2353/ajpath.2007.060665.

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Reiber, W., H. Nöschel, S. Schröder, and B. Müller. "Glucose and oxygen consumption, and lactate production of human placentae dually perfused in vitro under normoxia, hypoxia, and reoxygenation after a hypoxic period." Placenta 10, no. 5 (September 1989): 476. http://dx.doi.org/10.1016/0143-4004(89)90098-2.

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Curtis, Daniel J., Aman Sood, Tom J. Phillips, Veronica H. L. Leinster, Akihiro Nishiguchi, Christopher Coyle, Lizeth Lacharme-Lora, et al. "Secretions from placenta, after hypoxia/reoxygenation, can damage developing neurones of brain under experimental conditions." Experimental Neurology 261 (November 2014): 386–95. http://dx.doi.org/10.1016/j.expneurol.2014.05.003.

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Hung, T. H., S. F. Chen, J. D. Liou, J. J. Hsu, M. J. Li, Y. L. Yeh, and T. T. Hsieh. "Bax, Bak and Mitochondrial Oxidants are Involved in Hypoxia-reoxygenation-induced Apoptosis in Human Placenta." Placenta 29, no. 7 (July 2008): 565–83. http://dx.doi.org/10.1016/j.placenta.2008.03.005.

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Dai, Hu, and Xianmei Lu. "MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway." Open Medicine 17, no. 1 (January 1, 2022): 2062–71. http://dx.doi.org/10.1515/med-2022-0617.

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Abstract Preeclampsia (PE) is a common pregnancy-specific syndrome with an incidence of 4.6% in all pregnant women. Numerous studies have uncovered the functions and mechanisms of microsomal glutathione transferase 1 (MGST1) in different diseases and cellular processes, but whether MGST1 plays a role in PE remains unclear. Our study aimed to investigate the regulatory role of MGST1 in PE progression. In this study, the HTR8/SVneo cells were incubated with CoCl2 (250 µM) to mimic hypoxia in trophoblasts. Real-time quantitative polymerase chain reaction revealed that MGST1 was dramatically reduced in the placenta of PE patients. The proliferation of HTR8/SVneo cells was assessed via the Cell Counting Kit-8 and colony formation assays, and the results showed that MGST1 upregulation increased the cell viability of HTR8/SVneo cells. In addition, wound healing and Transwell assays unveiled that the elevation of MGST1 enhanced trophoblast cell migration and invasion. Moreover, the upregulation of MGST1 alleviated the hypoxia-induced oxidative stress in trophoblast cell. Mechanically, we found that MGST1 regulated PE progression by activating the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. In conclusion, MGST1 alleviated the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promoted cell proliferation, migration, and invasion via the activation of the PI3K/AKT/mTOR pathway in PE. These results suggested that MGST1 can be a potential target for the prevention and treatment of PE.

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Leinster, Veronica H. L., Thomas J. Phillips, Nicola Jones, Sharon Sanderson, Katja Simon, Jon Hanley, and Charles Patrick Case. "Cortical cells are altered by factors including bone morphogenetic protein released from a placental barrier model under altered oxygenation." Neuronal Signaling 4, no. 1 (April 2020). http://dx.doi.org/10.1042/ns20190148.

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Abstract Episodes of hypoxia and hypoxia/reoxygenation during foetal development have been associated with increased risk of neurodevelopmental conditions presenting in later life. The mechanism for this is not understood; however, several authors have suggested that the placenta plays an important role. Previously we found both placentas from a maternal hypoxia model and pre-eclamptic placentas from patients release factors lead to a loss of dendrite complexity in rodent neurons. Here to further explore the nature and origin of these secretions we exposed a simple in vitro model of the placental barrier, consisting of a barrier of human cytotrophoblasts, to hypoxia or hypoxia/reoxygenation. We then exposed cortical cultures from embryonic rat brains to the conditioned media (CM) from below these exposed barriers and examined changes in cell morphology, number, and receptor presentation. The barriers released factors that reduced dendrite and astrocyte process lengths, decreased GABAB1 staining, and increased astrocyte number. The changes in astrocytes required the presence of neurons and were prevented by inhibition of the SMAD pathway and by neutralising Bone Morphogenetic Proteins (BMPs) 2/4. Barriers exposed to hypoxia/reoxygenation also released factors that reduced dendrite lengths but increased GABAB1 staining. Both oxygen changes caused barriers to release factors that decreased GluN1, GABAAα1 staining and increased GluN3a staining. We find that hypoxia in particular will elicit the release of factors that increase astrocyte number and decrease process length as well as causing changes in the intensity of glutamate and GABA receptor staining. There is some evidence that BMPs are released and contribute to these changes.

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Gu, Mengqi, Fengyuan Zhang, Xiaotong Jiang, Pengzheng Chen, Shuting Wan, Qingfeng Lv, Yuan Lu, Qian Zhou, Yanyun Wang, and Lei Li. "Influence of placental exosomes from early onset preeclampsia women umbilical cord plasma on human umbilical vein endothelial cells." Frontiers in Cardiovascular Medicine 9 (December 23, 2022). http://dx.doi.org/10.3389/fcvm.2022.1061340.

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BackgroundEarly onset preeclampsia (EOSP, PE) is characterized by hypertension, proteinuria, and endothelial dysfunction. Oxidative stress-induced trophoblast dysfunction is a major pathology in PE. Placental exosomes are extracellular vesicles that are involved in “mother-placenta-foetal communication” and can regulate the biological functions of endothelial cells. Our study was designed to evaluate placental exosomes effects on endothelial cells.MethodsUmbilical cord blood from normal pregnant women and patients with PE were collected. A hypoxia/reoxygenation (H/R) model in human first trimester extravillous trophoblast cell (HTR8/SVneo) line to simulate the PE model of oxidative stress in vitro. Then, placental exosomes (i.e., NO-exo, H/R-exo, N-exo, and PE-exo) were extracted and identified. Finally, the effects of placental exosomes on the biological functions of human umbilical vein endothelial cells (HUVECs) were further evaluated by performing a series of experiments.ResultsPlacental exosomes had a double-membrane cup structure with diameters of 30–150 nm, and there was no obvious difference in placental exosomes. Compared with NO-exo and N-exo, H/R-exo and PE-exo inhibited HUVECs proliferation, tube formation and migration, increased permeability and apoptosis in vitro.ConclusionWe hypothesize that H/R-exo and PE-exo impair vessel development by disrupted biological functions in endothelial cells, which may result in vascular disorders in offspring.

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Mukherjee, Indrani, Ruby Dhar, Sunil Singh, Jai Bhagwan Sharma, Tapas Chandra Nag, Asit Ranjan Mridha, Parul Jaiswal, Subhrajit Biswas, and Subhradip Karmakar. "Oxidative stress-induced impairment of trophoblast function causes preeclampsia through the unfolded protein response pathway." Scientific Reports 11, no. 1 (September 16, 2021). http://dx.doi.org/10.1038/s41598-021-97799-y.

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AbstractPre-eclampsia (PE) is a pregnancy-specific disorder, characterized by hypertension and proteinuria. In PE, trophoblasts mediated inadequate remodeling of uterine spiral arteries seem to interrupt uteroplacental blood flow, one of the hallmarks in the early onset of PE (EO-PE). This, in turn, results in placental ischemia–reperfusion injury during hypoxia and reoxygenation episodes, leading to the generation of reactive oxygen species (ROS) and oxidative stress (OS). But still it is debatable if OS is a cause or consequence of PE. In this present study, we have investigated the effects of OS on PE placentae and trophoblast cell functions using BeWo and HTR8/SVneo cell lines. PE placental tissues showed abnormal ultrastructure, high level of reactive oxygen species (ROS) with altered unfolded protein responses (UPR) in compare with term placental tissues. Similar to PE placentae, during OS induction, the trophoblast cells showed altered invasion and migration properties with significantly variable expression of differentiation and invasion markers, e.g., syncytin and MMPs. The effect was rescued by antioxidant, N-acetyl cysteine, thereby implying a ROS-specific effect and in the trophoblast cells, OS triggers UPR pathway through IRE1α-XBP1 axis. Taken together, these findings highlight the harmful effect of unfolded protein response, which was induced due to OS on trophoblast cells and deformed invasion and differentiation programme and can be extended further to clinical settings to identify clinically approved antioxidants during pregnancy as a therapeutic measure to reduce the onset of PE.

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Liang, Yue, Ping Wang, Yueyang Shi, Bihong Cui, and Jinlai Meng. "Long noncoding RNA maternally expressed gene 3 improves trophoblast dysfunction and inflammation in preeclampsia through the Wnt/β-Catenin/nod-like receptor pyrin domain-containing 3 axis." Frontiers in Molecular Biosciences 9 (October 14, 2022). http://dx.doi.org/10.3389/fmolb.2022.1022450.

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Inadequate trophoblastic infiltration and resulting placental hypoxia and inflammation comprise the core pathological basis of preeclampsia (PE). Maternally expressed gene 3 (MEG3) is known to be involved in the pathogenesis of preeclampsia by inhibiting the migration and invasion of trophoblasts and promoting their apoptosis. Nevertheless, the specific underlying downstream molecular mechanism of MEG3 is less well characterized. In this study, we detected lower expression levels of MEG3 and β-Catenin and higher expression of nod-like receptor pyrin domain-containing 3 (NLRP3) in placental tissues of pregnant women with severe preeclampsia (sPE) than in normal pregnancies. Elevated serum levels of IL-1β and TNF-α were also observed in the sPE group. Then, we established a hypoxia/reoxygenation (H/R) model to mimic preeclampsia. Similar results with sPE group were found in the H/R group compared with the control group. In addition, suppressive trophoblast proliferation, migration and invasion and increases in the apoptotic rate and inflammation were also detected in the H/R group. Notably, overexpressing MEG3 markedly improved trophoblast dysfunction and inflammation caused by H/R. However, the effects of MEG3 on trophoblasts, whether upregulated or downregulated, can be reversed by DKK-1 (Wnt/β-Catenin inhibitor) and MCC950 (NLRP3 inhibitor). The current study revealed that MEG3 regulates trophoblast function and inflammation through the Wnt/β-Catenin/NLRP3 axis and provided new insights into the pathogenesis of preeclampsia.

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Zhao, Xiaolan, Xun Zhang, Zhao Wu, Jie Mei, Lingling Li, and Yujue Wang. "Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome." Molecular Medicine 27, no. 1 (July 23, 2021). http://dx.doi.org/10.1186/s10020-021-00335-x.

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Abstract Objective Numerous studies have confirmed the correlation of microRNAs (miRNAs) with human disease, yet few have explored the role of miR-135 in preeclampsia (PE). This study intends to discuss miR-135’s function in inflammatory response in PE by modulating proprotein convertase subtilisin/kexin-6 (PCSK6) and NLR pyrin domain containing 3 (NLRP3). Methods The venous blood and placental tissues were collected from PE pregnant women and 25 normal ones. The levels of miR-135, PCSK6 and NLRP3 in placenta tissues of patients were detected. Hypoxia/reoxygenation HTR-8/SVneo and HPT-8 models were established to mimic PE in vitro, and cell proliferation, colony formation, apoptosis rate, invasion, migration and inflammation were detected through gain-of and loss-of-function assays. Results MiR-135 was down-regulated, and PCSK6 and NLRP3 were up-regulated in PE patients. Up-regulating miR-135 or silencing PCSK6 strengthened colony formation ability, viability, invasion and migration ability, and weakened apoptosis and inflammation of H/R-treated HTR-8/SVneo and HPT-8 cells. Inhibition of NLRP3 negated the effects of silenced PCSK6 in H/R-treated HTR-8/SVneo and HPT-8 cells. Conclusions Altogether, we demonstrate that up-regulated miR-135 or reduced PCSK6 attenuates inflammatory response in PE by restricting NLRP3 inflammasome, which provides novel therapy for PE treatment.

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Zheng, Xiaoguo, Weibin Wu, Qian Zhou, Yahan Lian, Yuqian Xiang, and Xinzhi Zhao. "Targeted bisulfite resequencing of differentially methylated cytosines in pre-eclampsia reveals a skewed dynamic balance in the DNA methylation of enhancers." Clinical Science, January 16, 2023. http://dx.doi.org/10.1042/cs20220644.

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Pre-eclampsia (PE) is a major hypertensive disorder of pregnancy. Widespread differentially methylated cytosines (DMCs) with modest changes in methylation level are associated with PE, whereas their cause and biological significance remain unknown. We aimed to clarify DNA methylation patterns around DMCs in 103 placentas using MethylCap targeted bisulfite re-sequencing (MethylCap-seq) assays of 690 selected DMCs. We verified the MethylCap-seq method, then validated 677 (98.1%) of DMCs (vDMCs) in an independent cohort. The validated DMCs were strongly enriched in active placenta-specific enhancers and showed highly dynamic methylation levels. We found high epigenetic heterogeneity between vDMCs and adjacent CpG sites (r2 < 0.2) and a significant decrease in PE in the discovery and replication cohorts (p = 2.00×10-24 and 6.43×10-9, respectively). We replicated the methylation changes in a hypoxia/reoxygenation cell model. We constructed 112 methylation haplotype blocks and found that the frequencies of unmethylated haplotypes (UMHs) were dynamic with gestational age (GA) and were altered in maternal plasma of patients with PE. Our results uncovered additional DNA methylation features in PE placentas and suggested a model of skewed DNA methylation balance of enhancers in PE.

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Journal articles on the topic 'Placental hypoxia/reoxygenation'

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