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Centre for Trophoblast Research


Supervisor: Professor Dino Giussani

Preeclampsia is a leading cause of maternal and fetal death in the UK, imposing a substantial burden on our nation’s health and wealth. Despite this, the physiological mechanisms underlying preeclampsia are poorly understood, partly because the current overall consensus is that the disease is multi-factorial in nature, involving vascular, genetic, immunological and/or environmental factors.  What is accepted is that in preeclampsia there is inadequate invasion of the maternal uterine spiral arteries into the placental trophoblast. This results in poor placental perfusion and leads to placental and fetal hypoxia. Hypoxia is a potent stimulus for endothelial dysfunction and, during pregnancy, it promotes intrauterine growth retardation. Placento-fetal hypoxia may therefore provide a suitable stimulus linking the adverse effects of pre-eclampsia on the vascular physiology of the mother, the placenta and the unborn child. One mechanism via which placento-fetal hypoxia may affect several circulations is through the activation of oxidative stress. Generation of reactive oxygen species, such as the superoxide anion, sequester nitric oxide reducing its bioavailability and thereby promote endothelial dysfunction. Interestingly, markers of oxidative stress are elevated in the placenta and circulation of affected women.

At the University of Cambridge, we have created 4 bespoke isobaric hypoxic chambers able to maintain pregnant sheep for the duration of gestation under controlled hypoxic conditions.  We have also developed a bespoke wireless data acquisition system able to record pressure and blood flow signals from mother and fetus while the hypoxic pregnancy is developing.  In this PhD, we will exploit these facilities to measure for the first time continuous in vivo changes in maternal blood pressure, maternal heart rate, uterine blood and vascular resistance, fetal arterial blood pressure, fetal heart rate and fetal umbilical arterial blood flow and vascular resistance in control and chronically hypoxic pregnancy.  The maternal and fetal cardiovascular data will be paralleled by daily assessment of maternal and fetal arterial blood gas and metabolic status.  Maternal daily urine samples will also be taken for protein analysis.  At the end of control or hypoxic pregnancy, samples of the placenta will be fixed and frozen for histological and molecular analysis of oxidative stress.  Branches of the uterine arteries will be isolated and mounted on an in vitro wire myograph for assessment of changes in vasoconstrictor and vasodilator reactivity.  All experiments will be repeated in control and hypoxic pregnancy undergoing maternal treatment with different antioxidants.

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