(MRC DTP) Programming of pulmonary hypertension by prenatal hypoxia

Cardiovascular disease remains the leading cause of death worldwide. Despite significant advances in treatment, prevention strategies are the most cost-effective way to reduce the socio-economic burden of these diseases. Prevention has traditionally targeted behavioural and lifestyle risk factors, such as smoking and obesity. The seminal work of Barker1 demonstrated, however, that adverse events during pregnancy are strongly correlated with cardiovascular disease in adult offspring. A causal relationship is well-established, but the mechanistic basis for programmed cardiovascular dysfunction in offspring, and whether it can be prevented by intervention in early life, remains poorly understood.

Insufficient oxygen supply to an embryo/foetus (developmental hypoxia) occurs in a wide range of complicated pregnancies, including pre-eclampsia, placental insufficiency, placental infection, maternal anaemia, gestational diabetes and high altitude pregnancy. At birth, the pulmonary circulation undergoes rapid, profound structural and functional changes, which shift the location of gas exchange from the placenta to the lung. The process depends partly on blood oxygen levels and can be disrupted by exposure to hypoxia in the perinatal period. The pulmonary circulation can be permanently changed, so that prenatal hypoxia leads to abnormal pulmonary vascular reactivity as an adult. This has been demonstrated in humans, sheep and rats2,3,4. Similar effects are seen in offspring from pre-eclamptic mothers and pregnancies generated by assisted reproductive technologies5, suggesting that pre-natal hypoxia leads to foetal programming that alters pulmonary artery function. These changes occur despite the offspring being maintained postnatally in a normoxic environment, suggesting that developmental hypoxia programmes a dysfunctional phenotype in the offspring that cannot be reversed by normalising oxygen availability after birth.

Importantly, impaired cardiac function in offspring from hypoxic pregnancies can be prevented by maternal treatment with antioxidants to curtail reactive oxygen species (ROS) generation, but their ability to restore pulmonary vascular function is unknown. Hypoxia is a potent stimulus for ROS generation, so developmental hypoxia promotes oxidative stress in the foetus. There is great interest in identifying a translational antioxidant therapy that can be given to pregnant women in tolerable doses to rescue hypoxia-induced cardiovascular dysfunction in the offspring.

This project will investigate the functional changes that give rise to pulmonary vascular dysfunction in the offspring of rodent dams subjected to controlled periods of hypoxia during pregnancy. Function will be studied at the artery, cell and molecular level. Melatonin, an antioxidant thought to be safe in pregnancy, will also be investigated for its ability to reverse the identified changes.

Dr Gina Galli: https://www.research.manchester.ac.uk/portal/Gina.Galli.html
Prof. Alison Gurney: https://www.research.manchester.ac.uk/portal/alison.gurney.html

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.