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Graham Burton FMedSci

Placental development and function.
Graham Burton, FMedSci

Mary Marshall and Arthur Walton Professor of the Physiology of Reproduction

Director of Centre for Trophoblast Research

Graham Burton is accepting applications for PhD students.

Office Phone: +44 (0) 1223 333856, Fax: +44 (0) 1223 333840

Research Interests

Our focus is on human placental development, and the involvement of the placenta in complications of pregnancy such as miscarriage, fetal growth restriction and pre-eclampsia. In particular, we are interested in the effects of oxygen, hypoxia, and oxidative and endoplasmic reticulum stress on trophoblast differentiation and function. This interest stems from our finding, in collaboration with Professor Eric Jauniaux, that the maternal arterial circulation to the placenta is not fully established until towards the end of the first trimester of pregnancy. We demonstrated that prior to this time the conceptus is supported by secretions from the endometrial glands, histotrophic nutrition, that are delivered into the intervillous space through the developing basal plate. Consequently early development takes place in a physiologically low oxygen environment, and there is a threefold increase in the intraplacental oxygen concentration at the start of the second trimester, the oxygen transition. Currently, we are investigating how the placenta may stimulate its own development during early pregnancy by signalling to the endometrial glands and upregulating their secretion of growth factors and nutrients.

Our research has shown that fluctuations in oxygenation are particularly damaging to the trophoblast, leading us to propose ischaemia-reperfusion as the primary placental insult when trophoblast invasion and spiral artery remodeling are deficient. Recent work has elucidated the signalling pathways activated by that stress, leading to changes in gene transcript profiles and cytokine secretion that may stimulate the development of pre-eclampsia. We have also provided the first evidence that the syncytiotrophoblast is vulnerable to endoplasmic reticulum stress, describing a spectrum of changes from homeostatic adaptations to low oxygen in healthy high-altitude pregnancies to frank pathology in cases of fetal growth restriction. Most recently, we have shown that the placental molecular pathology is strikingly different in cases of early-onset pre-eclampsia compared to late-onset cases, demonstrating that the syndrome is heterogeneous and has different aetiologies.

Key advances of the group since 2005

2005: Identified that phylogenetically old carbohydrate metabolic (polyol) pathways are highly active during the first trimester when the intraplacental oxygen concentration is low.

2006: Demonstrated that fetal cell-free DNA is released from the placenta through apoptotic pathways

2007: Demonstrated that labour induces oxidative stress and transcriptional changes in the placenta that mimic those seen in pre-eclampsia

2008: First identification that endoplasmic reticulum stress contributes to the placental pathophysiology of intrauterine growth restriction

2009: First demonstration that a proportion of the nuclei within the syncytiotrophoblast are transcriptionally active

2010: Identified a transcriptional network that may define a trophoblast stem cell population within the placenta

2011: Identified that soluble FLT1 sensitises endothelial cells to pro-inflammatory cytokines, a potential mechanism in pre-eclampsia

2012: First demonstration that endoplasmic reticulum stress compromises mitochondrial function through inhibition of synthesis of MTC complexes

2013: First demonstration that hydrogen sulphide is a potent placental vasodilator, and that production is impaired in pathological placentas with increased vascular resistance

2014: First demonstration of the heterogeneity of placental molecular pathology in pre-eclampsia

2015: Identified that different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast

Funding: MRC, Wellcome Trust Programme grants, Anatomical Society, Action Medical Research, Evelyn Trust

Key Publications

Fogarty NME, Burton GJ, Ferguson-Smith AC, (2015), Different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast of the human placenta, Placenta, 36, 796-802

Burton GJ, Fowden AL, (2015), The placenta; a multifaceted, transient organ, Philosophical Transactions of the Royal Society B, 370, 21040066

Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ, (2014), Differential activation of placental Unfolded Protein Response pathways implies heterogeneity of causation of early- and late-onset pre-eclampsia, Journal of Pathology, 234, 262-276

Cindrova-Davies T, Herrera EA, Niu Y, Kingdom J, Giussani DA, Burton GJ, (2013), Reduced cystathionine g-lyase and increased miR-21 are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator, American Journal of Pathology, 182, 1448-1458

Benirschke K, Burton GJ, Baergen R, (2012), Pathology of the Human Placenta, 6th edition, Springer, Berlin, pp. 941

Above: Placental villi from a normal term placenta showing increased levels of oxidative stress following exposure to hypoxia-reoxygenation in vitro. The syncytiotrophoblast covering of the villi shows co-localisation (orange) of hydoxynonenal (green), a marker of lipid peroxidation, and the vasoconstrictor, endothelin (red). Nuclei are stained by DAPI (blue). Placental oxidative stress is thought to be a key mediator in the development of pre-eclampsia, stimulating the release of factors that cause maternal endothelial cell activation. Image courtesy of Dr Cindrova-Davies.

Above: The microvasculature of a terminal villus from a mature human placenta outlined by a fluorescent dye that binds to the fetal endothelial cells. Nuclei of the overlying syncytiotrophoblast are stained by DAPI (blue). The complex branching and localised dilations of the capillaries ensures efficient exchange between the maternal and fetal circulations. Image courtesy of Dr Skepper.