Fetal Programming of Coronary Artery Disease

描述（由申请人提供）：心血管疾病是美国和其他发达国家的主要死亡原因。仅在美国，每年就有大约100万人死于心血管疾病，占所有死因的近50%。除了已知的心血管疾病相关危险因素外，过去十年的研究表明，胎儿期的影响可能易患冠心病。胎儿适应母体和环境对心血管疾病的影响存在许多潜在机制，包括代谢和内分泌功能、器官和组织结构以及基因表达的改变。肾素-血管紧张素系统与内皮功能障碍的发展和动脉粥样硬化的进展密切相关。先前对胎儿编程的研究表明，肾素-血管紧张素系统的关键基因上调，血管紧张素II的作用增强。我们推测，冠状血管肾素-血管紧张素系统的上调是胎儿编程的一个重要方面，导致氧化应激增加，最终导致冠状动脉内皮功能障碍和冠状动脉疾病。我们计划使用一个成熟的胎儿编程模型，即胎儿绵羊产前早期暴露于地塞米松，以进一步探索这一假设。环境对胎盘功能的影响导致胎儿暴露于糖皮质激素的增加似乎是胎儿编程的重要机制。本研究的具体目的是证明，在产前暴露于地塞米松后，1)冠状动脉血管紧张素II受体基因表达上调，2)冠状动脉血管反应性改变，特别是对血管紧张素的反应，3)血管氧化应激增强，4)血管基因表达谱不同。我们认为这些差异在生命早期就存在，并在整个发展过程中持续存在。早期地塞米松暴露对冠状动脉血管功能和血管基因表达的影响的研究可能为不良宫内环境与随后动脉粥样硬化的发展之间提供重要的联系。了解这些联系以及胎儿环境改变导致成年期疾病的具体机制具有重要的全球公共卫生意义。只有在发展过程的背景下了解高血压和心血管疾病的原因和机制，才有可能制定初级预防战略。

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.