Animal Models of Pre-eclampsia

Sunderland, Neroli; Hennessy, Annemarie; Makris, Angela

doi:10.1111/j.1600-0897.2010.00929.x

Cited by 41 publications

(41 citation statements)

References 65 publications

(74 reference statements)

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“…However, other studies have shown that the peak insulin dose in type 1 diabetes occurs later in the third trimester, between 32 and 37 weeks (2,8,26,38,39). In keeping with this, our study, which also included women with type 2 diabetes, showed the peak insulin dose was reached at 34 weeks (31)(32)(33)(34)(35)(36) in the falling insulin requirement group and 37 weeks (35-38) in the control subjects. Calculating the change in insulin dose from 30 weeks rather than the peak dose may therefore underestimate the fall in requirements.…”

Section: Discussionsupporting

confidence: 71%

“…Preeclampsia therefore provides insight into the possible mechanisms implicated in the pathogenesis of falling insulin requirements. Animal and human studies suggest that an exaggerated inflammatory response and other factors causing suboptimal placentation in early pregnancy can lead to release of antiangiogenic factors, causing the preeclampsia syndrome later in pregnancy (29)(30)(31). Women with diabetes are more likely to have a hypoxic and proinflammatory intrauterine environment due to underlying vascular disease and particularly in the setting of poor glycemic control (32).…”

Section: Discussionmentioning

confidence: 99%

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Falling Insulin Requirements Are Associated With Adverse Obstetric Outcomes in Women With Preexisting Diabetes

2014

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OBJECTIVETo investigate the clinical significance of falling insulin requirements in women with preexisting or overt diabetes in pregnancy. RESEARCH DESIGN AND METHODSA retrospective review of 139 pregnancies was conducted in women, with preexisting diabetes, delivering between January 2010 and January 2013. Women with falling insulin requirements of 15% or more from the peak total daily dose in late pregnancy were considered case subjects (n = 35). The primary outcome consisted of a composite of clinical markers of placental dysfunction, including preeclampsia, small for gestational age (SGA, £5th percentile for gestational age), stillbirth (>20 weeks), and premature delivery (£30 weeks). RESULTSA total of 25.2% of women had >15% fall in insulin requirements with nulliparity as the only predictor at baseline (odds ratio [OR] 2.5 [95% CI 1.1-5.7], P = 0.03). Falling insulin requirements were associated with an increased risk of preeclampsia (OR 3.5 [1.1-10.7], P < 0.05) and the composite of clinical markers of placental dysfunction (4.4 [1.73-11.26], P = 0.002). Although falling insulin requirements were associated with higher rates of SGA (3.4 [1.0-11.3], P = 0.048), they were not associated with other adverse neonatal outcomes. However, there was a higher incidence of neonatal intensive care unit admission (15.5 [3.1-77.6], P = 0.001) and earlier delivery in this group (median 37.7 weeks ], P = 0.014). CONCLUSIONSFalling insulin requirements, in women with preexisting diabetes, are associated with an increased risk of complications related to placental dysfunction. Further prospective studies are needed to guide clinical management.Falling insulin requirements in late pregnancy are thought to signify feto-placental compromise, often prompting admission to hospital for maternal and fetal monitoring as well as emergency delivery in some cases (1). Most women with preexisting diabetes experience an increase in insulin requirements during the second half of pregnancy (2) to maintain euglycemia, in light of a 50-70% rise in insulin resistance (3). Because insulin resistance is driven by placental-mediated hormone production, including human placental lactogen (hPL), cortisol, and progesterone

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Falling Insulin Requirements Are Associated With Adverse Obstetric Outcomes in Women With Preexisting Diabetes

2014

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“…However, the ideal animal model of pre-eclampsia does not exist, in part because the spontaneous development of pre-eclampsia during pregnancy is a condition largely unique to humans [39,40]. To mimic the human syndrome a model would need to be characterized by the development of pregnancy-specific hypertension, proteinuria and associated alterations in vascular function and biomarkers.…”

Section: The In Utero Insultmentioning

confidence: 99%

Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies

et al. 2012

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Pre-eclampsia is increasingly recognized as more than an isolated disease of pregnancy. Women who have had a pregnancy complicated by pre-eclampsia have a 4-fold increased risk of later cardiovascular disease. Intriguingly, the offspring of affected pregnancies also have an increased risk of higher blood pressure and almost double the risk of stroke in later life. Experimental approaches to identify the key features of pre-eclampsia responsible for this programming of offspring cardiovascular health, or the key biological pathways modified in the offspring, have the potential to highlight novel targets for early primary prevention strategies. As pre-eclampsia occurs in 2–5% of all pregnancies, the findings are relevant to the current healthcare of up to 3 million people in the U.K. and 15 million people in the U.S.A. In the present paper, we review the current literature that concerns potential mechanisms for adverse cardiovascular programming in offspring exposed to pre-eclampsia, considering two major areas of investigation: first, experimental models that mimic features of the in utero environment characteristic of pre-eclampsia, and secondly, how, in humans, offspring cardiovascular phenotype is altered after exposure to pre-eclampsia. We compare and contrast the findings from these two bodies of work to develop insights into the likely key pathways of relevance. The present review and analysis highlights the pivotal role of long-term changes in vascular function and identifies areas of growing interest, specifically, response to hypoxia, immune modification, epigenetics and the anti-angiogenic in utero milieu.

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“…Many methods are used to establish preeclampsia-like animal models to investigate the etiology, pathogenesis and treatment of preeclampsia, including uterine artery ischemia, angiogenesis disorders, nitric oxide synthase inhibitors, endotoxin injection, inflammatory factor injections and genetic defects [18]. Although these preeclampsia-like animal models can explain the relationship between one factor and the etiology or pathogenesis of preeclampsia, they lack relevance in the study of multiple pathogenic factors associated with preeclampsia.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Long Chain Fatty Acid Oxidation Related Enzyme Changes in Different Preeclampsia-Like Mouse Models

Ding¹,

Yang²

2013

J Hypertens

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IntroductionPreeclampsia is a serious obstetric complication and a major cause of maternal and perinatal mortality and its pathogenesis is still unclear. We and other researchers have proven that long-chain Fatty Acid Oxidation (FAO) is associated with some forms of preeclampsia.Most fatty acids in the human body are long-chain fatty acids. The β-oxidation of fatty acids occurs in the mitochondria. After activation of long-chain fatty acids, they need assistance from carnitine as a carrier and catalysis of carnitine palmitoyltransferase I (CPT I) in the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) in the inner mitochondrial membrane to enter into the mitochondria [1]. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) is a component of the mitochondrial trifunctional protein and is capable of catalyzing the third step of β-oxidation [2]. So CPT I, CPT II and LCHAD are key enzymes in the long-chain FAO process, and defects or dysfunction of which can result in disorders in longchain fatty acid transport into the mitochondria or oxidation, further resulting in inefficient energy release from FAO and affecting cell function.In a normal pregnancy, prolactin and estrogen increase the activity of hormone sensitive lipase, resulting in increased fat mobilization, increased maternal plasma Free Fatty Acids (FFA) and increased hepatic uptake of fatty acids. In the past, FAO was generally considered unimportant in placental and fetal development; however, a recent study found that this was not the case. Shekhawat et al. found that LCHAD and six other fatty acid β-oxidation enzymes were abundantly expressed in the placenta, indicating the long-chain FAO played an important role in placental development and energy supply [3]. Oey et al. found Very Long Chain Acyl-Coenzyme a Dehydrogenase (VLCAD) and LCHAD mRNA highly expressed during different stages in the embryo and fetal heart, liver and other tissues, and there were strong VLCAD, LCHAD and CPT II enzyme activities [4]. So long-chain FAO exists not only in the placenta, but also in embryonic tissues, and plays an important role in early development of the fetus. Thus, in a normal pregnancy placental and fetal development also requires FAO as an energy supply.Previous studies have found that LCHAD was associated with some forms of preeclampsia. Bartha and colleagues reported that LCHAD mRNA expression decreased in the placenta of preeclampsia patients compared with controls, and that the FAO ability of the placenta in preeclampsia patients was reduced [5]. Robinson et al. found that the plasma of preeclampsia patients could lead to lipid droplet aggregation in cultured human umbilical vein endothelial cells and decreased mitochondrial dehydrogenase activity [6]. In our previous studies we also found LCHAD expression decreased in the placenta with earlyonset severe preeclampsia, but there was no significant difference between late-onset preeclampsia and the control groups [7]. In animal experiments, we found that LCHAD expression was signifi...

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Animal Models of Pre-eclampsia

Cited by 41 publications

References 65 publications

Falling Insulin Requirements Are Associated With Adverse Obstetric Outcomes in Women With Preexisting Diabetes

Falling Insulin Requirements Are Associated With Adverse Obstetric Outcomes in Women With Preexisting Diabetes

Pre-eclampsia and offspring cardiovascular health: mechanistic insights from experimental studies

Mitochondrial Long Chain Fatty Acid Oxidation Related Enzyme Changes in Different Preeclampsia-Like Mouse Models

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