| 1. |
- Brook, Adam, et al.
(författare)
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Cell free hemoglobin in the fetoplacental circulation : A novel cause of fetal growth restriction?
- 2018
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Ingår i: FASEB Journal. - 0892-6638. ; 32:10, s. 5436-5446
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Tidskriftsartikel (refereegranskat)abstract
- Cell free hemoglobin impairs vascular function and blood flow in adult cardiovascular disease. In this study, we investigated the hypothesis that free fetal hemoglobin (fHbF) compromises vascular integrity and function in the fetoplacental circulation, contributing to the increased vascular resistance associated with fetal growth restriction (FGR). Women with normal and FGR pregnancies were recruited and their placentas collected freshly postpartum. FGRfetal capillaries showed evidence of erythrocyte vascular packing and extravasation. Fetal cord blood fHbF levels were higher in FGR than in normal pregnancies (P < 0.05) and the elevation of fHbF in relation to heme oxygenase-1 suggests a failure of expected catabolic compensation,which occurs in adults.During ex vivo placental perfusion, pathophysiological fHbF concentrations significantly increased fetal-side microcirculatory resistance (P<0.05). fHbF sequesteredNOinacute andchronic exposuremodels (P<0.001), andfHbF-primed placental endothelial cellsdevelopedaproinflammatoryphenotype,demonstratedby activationofNF-κBpathway, generation of IL-1α and TNF-α (both P < 0.05), uncontrolled angiogenesis, and disruption of endothelial cell flow alignment. Elevated fHbF contributes to increased fetoplacental vascular resistance and impaired endothelial protection.Thisunrecognizedmechanismfor fetal compromise offers a novel insight into FGRaswell as a potential explanation for associated poor fetal outcomes such as fetal demise and stillbirth.
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| 2. |
- Brownbill, Paul, et al.
(författare)
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An international network (PlaNet) to evaluate a human placental testing platform for chemicals safety testing in pregnancy
- 2016
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238. ; 64, s. 191-202
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Tidskriftsartikel (refereegranskat)abstract
- The human placenta is a critical life-support system that nourishes and protects a rapidly growing fetus; a unique organ, species specific in structure and function. We consider the pressing challenge of providing additional advice on the safety of prescription medicines and environmental exposures in pregnancy and how ex vivo and in vitro human placental models might be advanced to reproducible human placental test systems (HPTSs), refining a weight of evidence to the guidance given around compound risk assessment during pregnancy. The placental pharmacokinetics of xenobiotic transfer, dysregulated placental function in pregnancy-related pathologies and influx/efflux transporter polymorphisms are a few caveats that could be addressed by HPTSs, not the specific focus of current mammalian reproductive toxicology systems. An international consortium, “PlaNet”, will bridge academia, industry and regulators to consider screen ability and standardisation issues surrounding these models, with proven reproducibility for introduction into industrial and clinical practice.
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| 3. |
- Ejdesjö, Andreas, 1978-
(författare)
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Teratogenic Predisposition in Diabetic Rat Pregnancy
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pre-gestational diabetes increases the risk of congenital malformation in the offspring and both morbidity and mortality in the diabetic mother and her offspring. During pregnancy, high glucose levels act as a teratogen through several cellular and biochemical pathways and increased production of reactive oxygen species (ROS) has a central role in diabetic embryopathy. The aim of this work was to investigate the importance of genetic predisposition for congenital malformations and to study the genes involved in the teratogenic process of diabetic pregnancy.The crossbreeding of two rat strains, with both low and high incidence of diabetes-induced malformations, indicated that strain-specific maternal factors, such as disturbed serum levels of amino acids, triglycerides, and β-hydroxybutyrate, were associated with malformation. In addition, disturbed fetal expression of genes involved in ROS defense and development (Shh, Bmp4, Ret and Gdnf) in mandible and heart, and decreased activity of Gapdh and Aldose Reductase were associated with the teratogenic process, and the trans-generational heredity of the mother determined the type of malformations induced by maternal diabetes.In rat embryos, a diabetic environment in utero changed the expression of genes involved in ROS defense (Nrf2, Gpx1 and Cat), development of mandible and heart (Msx2, Shh, Bmp4, Ret and Gdnf), and neural tube closure and apoptosis (Pax3 and p53). The changes were divergent with tissue-specific alterations of gene expression in developing mandible, heart anlage, and whole embryo.Disruption of the Receptor for Advanced Glycation End products (RAGE) had a protective effect against diabetic embryopathy in mice, and the blockage of RAGE diminished ROS production in the offspring: this supported oxidative stress being a necessary etiological component in diabetic embryopathy.Maternal metabolic state and genetic susceptibility influence fetal outcome in experimental diabetic pregnancy. Disturbed protection against oxidative stress and tissue-specific derangements in the expression of developmental genes play pivotal roles in the teratogenic mechanism, and enhanced levels of Advanced Glycation End products (AGE) and RAGE-induced oxidative stress are involved in diabetic dysmorphogenesis.
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| 4. |
- Fröhlich, Julia D, et al.
(författare)
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Oxygen modulates the response of first-trimester trophoblasts to hyperglycemia
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 180:1, s. 153-164
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Tidskriftsartikel (refereegranskat)abstract
- Pregestational diabetes retards early embryonic growth. Placental and fetal growth are closely associated, suggesting that placental growth is also impaired. During the first trimester of gestation, oxygen tension rises steeply, leading to excessive production of reactive oxygen species (ROS), which is exacerbated in diabetes and may affect placental development. We hypothesized that oxygen modifies hyperglycemic effects on ROS formation, resulting in decreased first-trimester trophoblast growth. This was tested using a first trimester trophoblast-derived cell line (ACH-3P). Normoglycemia did not alter ACH-3P proliferation at 2.5%, 8%, and 21% oxygen. Hyperglycemic conditions for up to 3 days reduced cell number by 65% and resulted in cell cycle (G(1)- and S-phase) changes but only at 21% oxygen. Proliferation reduction could be partially restored by an inhibitor of mitogen-activated protein kinase (MAPK) ERK1/2 but not of Akt/PkB. Intracellular ROS elevation under hyperglycemia was oxygen independent, whereas mitochondrial superoxide levels were enhanced under hyperglycemia only at 21% oxygen. Intervention to modulate cytosolic and mitochondrial ROS, using ROS formation inducers and inhibitors, did not alter cell growth under hyperglycemia at 21% oxygen. The combination of hyperglycemia and high oxygen levels (21%) reduces proliferation of human first-trimester trophoblasts in a ROS-independent manner involving MAPK. This may account for reduced placental growth and, therefore, also for embryonic growth during the first-trimester pregestational diabetic pregnancies when the oxygen tension increases.
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| 5. |
- Hivert, Marie-France, et al.
(författare)
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Pathophysiology from preconception, during pregnancy, and beyond
- 2024
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 404:10448, s. 158-174
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Forskningsöversikt (refereegranskat)abstract
- Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.
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| 6. |
- König, Julia, 1983-, et al.
(författare)
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Amnion-derived mesenchymal stromal cells show angiogenic properties but resist differentiation into mature endothelial cells
- 2012
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Ingår i: Stem Cells and Development. - Rochelle, USA : Mary Ann Liebert. - 1547-3287 .- 1557-8534. ; 21:8, s. 1309-1320
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal cells derived from the human amnion (hAMSC) currently play an important role in stem cell research, as they are multipotent cells that can be isolated using noninvasive methods and are immunologically tolerated in vivo. The objective of this study was to evaluate their endothelial differentiation potential with regard to a possible therapeutic use in vascular diseases. hAMSC were isolated from human term placentas and cultured in Dulbecco's modified Eagle's medium (DMEM) (non-induced hAMSC) or endothelial growth medium (EGM-2) (induced hAMSC). Induced hAMSC changed their fibroblast-like toward an endothelial-like morphology, and were able to take up acetylated low-density lipoprotein and form endothelial-like networks in the Matrigel assay. However, they did not express the mature endothelial cell markers von Willebrand factor and vascular endothelial-cadherin. Gene expression analysis revealed that induced hAMSC significantly downregulated pro-angiogenic genes such as tenascin C, Tie-2, vascular endothelial growth factor A (VEGF-A), CD146, and fibroblast growth factor 2 (FGF-2), whereas they significantly upregulated anti-angiogenic genes such as serpinF1, sprouty1, and angioarrestin. Analysis of protein expression confirmed the downregulation of FGF-2 and Tie-2 (27%±8% and 13%±1% of non-induced cells, respectively) and upregulation of the anti-angiogenic protein endostatin (226%±4%). Conditioned media collected from hAMSC enhanced viability of endothelial cells and had a stabilizing effect on endothelial network formation as shown by lactate dehydrogenase and Matrigel assay, respectively. In summary, endothelial induced hAMSC acquired some angiogenic properties but resisted undergoing a complete differentiation into mature endothelial cells by upregulation of anti-angiogenic factors. Nevertheless, they had a survival-enhancing effect on endothelial cells that might be useful in a variety of cell therapy or tissue-engineering approaches.
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