The prevalence of obesity has increased significantly over the last 30 years such that it is now more common worldwide to be overweight or obese than normal weight. As a result of this, increasing numbers of women are entering pregnancy overweight or obese. Obesity during pregnancy is associated with an increased risk of numerous negative obstetric outcomes including miscarriage, stillbirth, and neonatal mortality. Moreover, obesity is associated with an increased risk of women developing disorders of pregnancy such as gestational diabetes mellitus (GDM) and pre-eclampsia. These disorders are associated with the development of type 2 diabetes (T2D) and persistently high arterial blood pressure (hypertension) in the years after delivery. Hypertension is the number one risk factor for the development of cardiovascular disease (CVD), and CVD is the leading cause of death across the globe. Therefore, maternal obesity during pregnancy is associated with poor cardiometabolic health both during pregnancy and in later life.

Children of obese women are at an increased risk of both becoming obese themselves and developing hypertension and CVD. While some of this increased risk in the general population is attributable to a shared obesogenic postnatal environment, studies in both humans and animals reveal that it is also directly programmed by exposure to maternal obesity in utero. This forms part of the Developmental Origins of Health and Disease (DOHaD) hypothesis, which states that exposure to suboptimal environments during development programmes changes in long-term health. Together, this shows that maternal obesity during pregnancy is associated with poor cardiometabolic health in both mother and baby in the short and long-term, which will result in an increasing number of people suffering and dying from CVD. Therefore, it is paramount that interventions are developed in order to break the transgenerational cycle of obesity and cardiovascular dysfunction. Two interventions used in pregnancies complicated by GDM and that are being trialled in glucose-tolerant obese pregnancies are the application of an exercise intervention and the use of the glucose-lowering medication metformin. While evidence of improved maternal cardiometabolic function in response to these interventions has been found in human studies, longitudinal follow-up of children is limited.

The Ozanne group uses a well-established mouse model of maternal diet-induced obesity to investigate the effects of maternal obesity and glucose intolerance during pregnancy on the cardiometabolic health of both mother and baby. Using this model, the effects of maternal exercise and metformin intervention during pregnancy on the cardiometabolic health of both mother and offspring can be investigated.

Previous studies have found that maternal exercise intervention improves metabolic and cardiac function in young adult male offspring of obese dams but does not prevent the programming of hypertension. This is associated with improved metabolic health in the dam without a significant change in her adiposity. However, how obesity affects maternal cardiovascular function in pregnancy, and whether this is affected by exercise, has not previously been investigated in this model. In Chapter 3 of this thesis, evidence of impaired cardiovascular adaptation to pregnancy was identified in obese dams, although this did not result in overt cardiac dysfunction in late gestation. Maternal obesity also resulted in fetuses being growth-restricted, which is well established to be associated with poor long-term cardiometabolic health. Neither the impaired cardiovascular adaptation nor fetal growth restriction were rescued by maternal exercise.

Changes in the autonomic control of the heart, including an increase in sympathetic activity and a decrease in parasympathetic activity, are a common feature of heart failure. Previous studies have suggested that maternal obesity programmes changes in autonomic control of the offspring heart. In Chapter 4 of this thesis, a new protocol was developed to investigate the response of the heart to sympathetic stimulation in vivo. This protocol is a powerful tool that can be adapted to investigate the effects of maternal obesity during pregnancy on cardiovascular function in male and female offspring.

Metformin administration during obese pregnancy has been found to improve maternal metabolic health in both human and animal studies. However, metformin exposure in utero has been found to programme increased adiposity and metabolic dysfunction in male and female offspring of obese dams. No studies have been published investigating the impact of metformin exposure during obese pregnancy on the blood pressure and vascular function of offspring beyond childhood in humans, or at all in animals. Hypertension and CVD are age-related disorders and so the effect of gestational metformin on blood pressure and vascular function must be investigated in aged offspring in order to draw clinically relevant conclusions about its effects. In Chapter 5 of this thesis, it was found that combined exposure to maternal obesity and metformin in utero programmed hypertension in aged offspring. This was associated with sex-specific changes in vascular reactivity. This suggests that maternal metformin administration during pregnancy is detrimental to long-term offspring cardiovascular health and highlights the importance of including both male and female offspring in studies of developmental programming.

Overall, this thesis investigated the effects of obesity on cardiovascular function in both pregnant mothers and their offspring and developed a new protocol for the investigation of cardiovascular function in vivo. It also assessed the effects of exercise intervention on maternal cardiovascular adaptation to pregnancy, and of metformin intervention on long-term cardiovascular health in offspring. Developing effective interventions in obese pregnancy is paramount for improving the cardiometabolic health of the population, both in reducing the incidence of CVD and T2D in overweight and obese mothers, and in preventing the programming of obesity and cardiovascular dysfunction in their offspring.