Abstract

Heart disease is the greatest killer in the UK today, imposing a substantial burden on the nation’s health and wealth. In addition to the interaction between genetic makeup and lifestyle risk factors, another concept in determining susceptibility to heart disease has now become established – one of developmental programming. This states that a component of both the cardiovascular health we enjoy and the risk of heart disease in adult life can be predetermined before birth, not only by our genes but also by their interaction with the quality of the prenatal environment. The mechanisms underlying the developmental programming of cardiovascular disease in complicated pregnancy remain unknown, preventing the identification of potential therapeutic targets for clinical intervention. Prenatal hypoxia is a common feature of complicated pregnancy. Building on a wealth of human and experimental data, the work presents the thesis that oxidative stress underlies the molecular basis via which prenatal hypoxia contributes to the developmental programming of cardiovascular disease. Using an integrative approach at the systems, isolated organ, cellular and molecular levels the data show that reductions in oxygen delivery to the unborn can increase its risk of developing heart disease later in life, and that treatment of complicated pregnancies with antioxidants can protect against this. The work offers the potential for therapeutic targets for clinical intervention against a developmental origin of heart disease in risky pregnancy.