Developmental Programming of Cardiovascular Dysfunction by Chronic Intermittent Hypoxia (360G-Wellcome-109149_Z_15_A)

Cardiovascular disease remains the greatest killer in the world. The environment encountered in fetal life can exert a profound influence on an individual’s risk of cardiovascular disease; what is known as developmental programming. Understanding the mechanisms via which programming occurs may lead to preventative therapy. One common outcomes of complicated pregnancy is fetal exposure to chronic intermittent hypoxia (CIH). However, the mechanisms underlying fetal programming by CIH are not known. One potential mechanism is increased oxidative stress in the fetal cardiovascular system, established through reverse electron transport (RET) following re-oxygenation secondary to hypoxic succinate accumulation. The aim of this project is to isolate the effects of CIH with or without RET inhibition on programming of cardiovascular disease. Using an integrative approach, combining studies in vivo with those at the isolated organ, cellular, mitochondrial, molecular and metabolomic levels, this work will be carried out in the chicken. The chick embryo is the ideal species of choice, as it allows the direct effects of CIH to be isolated on the developing cardiovascular system while negating additional confounding effects of the challenge in decreasing maternal food intake and triggering changes in lactation, as it occurs in mammals.