Cardiovascular dysfunction in the hypoxic fetus: intervention by mitochondria-targeted antioxidants (renewal)

Heart disease can start before birth. In addition to genetic conditions, an adverse prenatal environment may increase the risk of fetal cardiac dysfunction in late gestation. How this happens has remained largely an enigma because of our inability to record and test continuous fetal cardiovascular function in vivo. Here, we combine technological and molecular advances never possible before to study cardiovascular mechanisms in the fetus in vivo in ovine pregnancy complicated by chronic fetal hypoxia - a common consequence of sub-optimal pregnancy. We hypothesise that chronic fetal hypoxia weakens fetal cardiovascular defences and renders the fetal heart susceptible to injury. Mechanisms involved include fetal mitochondria-derived oxidative stress with succinate accumulation. Therefore, mitochondria-targeted antioxidant therapy is cardio-protective. We adopt an integrative approach, combining unique facilities to study hypoxic pregnancy in sheep with novel wireless continuous recording of in vivo fetal cardiovascular function, novel fetal mitochondria ratiometric mass spectrometry and novel fetal metabolomics. The programme of work exploits the unique expertise of three senior co-applicants with established track records in fetal cardiovascular physiology, mitochondrial biology and molecular mechanisms.