Babies who have suffered from placental insufficiency resulting in intrauterine growth restriction (IUGR) are more vulnerable for metabolic and cardiovascular disease postnatally. However, the mechanisms underlying this increased risk are poorly understood. Adaptations made by the fetus in response to placental insufficiency changes the trajectory for cellular function with lifelong consequences. Fetal organs and systems must develop and prepare for an extrauterine environment which involves an abrupt change in oxygen and nutritional substrates. The fetal heart utilizes primarily glucose and lactate as fuel and transitions to primarily fatty acid metabolism postnatally. This shift to fatty acid oxidation occurs concomitant with a doubling in oxygen levels at birth. The physiological preparation of the myocardium for this transition to fatty acid oxidation is poorly understood and the consequences of a suboptimal intrauterine environment on these processes is not known. Umbilicoplacental embolization is a well-established, clinically relevant model of placental insufficiency in sheep. This model leads to fetal hypoxemia, hypoglycemia and intrauterine growth restriction and has been used to investigate the effect of IUGR on several organ systems. With respect to the heart, growth and maturation is slowed, though little is known about the effects on metabolic pathways. Postnatally, IUGR sheep have altered glucose tolerance and sensitivity. This metabolic change is likely to have been initiated in utero as IUGR fetal sheep have impaired glucose oxidation. To the best of our knowledge, nothing is known about the effect of IUGR on fatty acid processing. However, IUGR sheep have a tendency to be more obese compared to control sheep, suggesting lipid handling may also be altered by placental insufficiency. Alterations to lipid handling in utero could have lifelong consequences on cardiac function due to alterations in energy production. The goal of this project is to determine whether fatty acid metabolism is impacted by placental insufficiency using the umbilicoplacental embolization model in sheep. The mechanisms involved in fatty acid uptake and metabolism will be systematically examined using an array of techniques including live cell imaging, lipidomics, mitochondrial stress tests and gene and protein expression analysis. This study will determine how this prenatal stress alters cardiomyocyte metabolism and may guide future therapies for improving nutrition practices and/or cardiovascular health.
Using a clinically relevant model of placental insufficiency in sheep, this project seeks to determine the molecular mechanisms that underlie altered cardiomyocyte fatty acid metabolism. These studies will provide insight into how the intrauterine environment sets the trajectory for cardiac and metabolic dysfunction in adulthood.
