Fetal Programming of Coronary Artery Disease

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DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the United States and other developed countries. In the United States alone, approximately 1 million individuals die from cardiovascular disease each year, nearly 50% of deaths from all causes. In addition to known associated risk factors for cardiovascular disease studies from the last decade suggest that influences during fetal life may predispose to coronary heart disease. There exist a number of potential mechanisms linking fetal adaptations to maternal and environmental influences to cardiovascular disease, including alterations in metabolic and endocrine functions, organ and tissue structure and gene expression. The renin-angiotensin system has been closely linked the development of endothelial dysfunction and progression to atherosclerosis. Previous studies of fetal programming demonstrate upregulation of key genes of the renin-angiotensin system and enhanced action of angiotensin II. We hypothesize that upregulation of the renin-angiotensin system in the coronary vasculature is an important aspect of fetal programming, resulting in increased oxidative stress and ultimately coronary endothelial dysfunction and coronary artery disease. We plan to use a developed model of fetal programming namely early prenatal exposure to dexamethasone in fetal sheep to further explore this hypothesis. Increased fetal exposure to glucocorticoids resulting from environmental influences on placental function appears to be an important mechanism of fetal programming. The specific aims of this proposal are to demonstrate that following prenatal exposure to dexamethasone, 1) coronary artery angiotensin II receptor gene expression is upregulated, 2) coronary vascular reactivity is altered, particularly in response to angiotensin, 3) vascular oxidative stress is enhanced, and 4) vascular gene expression profiles differ. We propose these differences are present early in life and persist throughout development. Studies of the effects of early dexamethasone exposure on coronary vascular function and vascular gene expression may provide an important link between adverse intrauterine environment and the subsequent development of atherosclerosis. Understanding these links and the specific mechanisms by which the altered fetal environment leads to disease in adulthood has important, worldwide public health implications. Only when the causes and mechanisms of hypertension and cardiovascular disease are understood in the context of a developmental process will it be possible to develop strategies for primary prevention.