Maternal Obesity During Pregnancy: Translatable Programmed Cardiovascular Dysfunction in Offspring

Maternal obesity during pregnancy is an increasingly alarming health care issue with short and long term detrimental consequences for both mother and child. In her 2015 annual report, then as Chief Medical Officer, Dame Sally Davies highlighted that over half of women in the UK are over-weight or obese during pregnancy. She stressed that a focus on the health of the pregnant woman and of her offspring and interventions to improve it offers a new and important opportunity to ensure the physical and mental wellbeing of mothers and children. In humans, important interventional studies have focussed on maternal exercise in obese or overweight pregnancy. However, it will take many years to investigate the long-term outcomes of these studies. Hence, animal models are indispensable to provide mechanistic insights for the changes observed and inform the human longer-term follow up studies. The current project addresses this issue directly using a well characterised sheep model of maternal obesity during pregnancy. It will define mechanisms by which obesity during pregnancy influences risk of heart disease in the offspring and provide invaluable information on what interventions during pregnancy can prevent this effect. In contrast to rodents, such as mice and rats, which are born highly immature, in sheep and humans, the foetal heart and blood mature their structure and function at similar rates during development. Therefore, sheep are the ideal animal model to address these questions and make the research more relevant to the human clinical situation.

Goal of research
This project will mimic the human situation of obesity during pregnancy in sheep and determine how maternal obesity can harm the baby's heart and circulation and increase the risk of heart disease in the adult offspring. It will test a specific antioxidant drug as potential treatment during obese pregnancy to prevent this.

Potential benefit of research
The results may lead to the design of clinical drug therapies to combat the ill effects of maternal obesity on the baby's heart and circulation to dimmish the risk of heart problems in the offspring. Cardiovascular disease is the greatest killer in the UK today and early origins of cardiovascular disease, such as those imposed by maternal obesity during pregnancy on the unborn child, contribute to this. Therefore, the work offers robust plans designed to deliver realistic potential interventions to improve population health and improve the quality of life not only in obese women but also their children, thereby having a major clinical, economic and societal impact on health.

Obesity has reached epidemic proportions, including in women of reproductive age. Over half of women in the UK are now obese or overweight during pregnancy. This is of significant concern as obesity during pregnancy not only has detrimental effects on the mother, but also on the children. Evidence derived from human studies and from animal models shows that maternal obesity can markedly increase the risk of heart disease in the offspring, even when young and when the progeny are fed a healthy diet and they themselves do not become obese. This highlights that it is something about exposure of the embryo or fetus to an obesity environment during gestation itself that either triggers a fetal origin of cardiovascular dysfunction and/or increases the risk of heart disease in the adult offspring. Therefore, this project will test the hypothesis that maternal obesity during pregnancy promotes a fetal origin of heart disease via adverse mechanisms triggered by mitochondria-derived oxidative stress. Causality will be addressed directly using mitochondria-targeted antioxidant intervention with MitoQ. The hypothesis will be tested using an established ovine model of maternal obesity during pregnancy. In contrast to rats and mice, which are born highly immature, the timing of cardiovascular developmental milestones in sheep and humans is much more similar. Therefore, using sheep markedly improves the human clinical translation of the biomedical research. The work will adopt an integrative approach, combining experiments of in vivo cardiovascular function with those at the isolated organ, cellular and molecular levels in the pregnant mother, as well as in the fetal and adult offspring.