PRENATAL LOAD MODULATION OF CORONARY GROWTH AND FUNCTION

冠状动脉生长和功能的产前负荷调节

• 批准号: 8675870
• 负责人: GEORGE D GIRAUD
• 金额: $ 16.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8675870
• 关键词: Accounting; Adult; Affect; Age; Blood Vessels; Blood capillaries; Blood flow; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Count; Cell Proliferation; Cell Size; Coronary; Coronary Circulation; Data; Depressed mood; Development; Dimensions; Disease; Environment; Epidemiologic Studies; Fetal Growth Retardation; Fetal Heart; Fetus; Growth; Health; Heart; Heart Diseases; Hyperplasia; Knowledge; Lead; Life; MAP Kinase Modules; MEKs; Measures; Medicine; Mitogen-Activated Protein Kinase Kinases; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardium; Neonatal; Outcome; Perinatal; Plastics; Pregnancy; Preparation; Process; Rest; Sheep; Signal Pathway; Signal Transduction; Stress; Structure; Systolic Pressure; Time; Tissues; Work; capillary; density; fetal; heart function; hemodynamics; human FRAP1 protein; in utero; mTOR Signaling Pathway; meetings; mortality; premature; prenatal; pressure; research study; response

Cardiovascular disease is the leading cause of death in the developed world. Epidemiological studies have shown the profound importance that the prenatal period has on life-long health. A likely explanation for this relationship is that the late fetal period, a period of robust growth, determines the number of cardiomyocytes and the structure of the coronary vasculature for life. Adverse intrauterine conditions leading to fetal growth restriction alter cardiac load and compromise heart growth. While the ability of adult heart to adapt to cardiovascular disease is limited, the fetal heart is highly plastic, undergoing rapid adaptation to best meet intrauterine conditions. The number of fetal cardiomyocytes and the anatomical dimensions of the fetal coronary circulation are not fixed but can be changed, both up and down, by prenatal conditions. Unfortunately, fetal responses to sub-optimal intrauterine environments may not lead to favorable outcomes in the fetus or later in the adult. It will not be possible to understand the devastating effects of intrauterine growth retardation on the fetal myocardium unless we deliberately study cardiomyocyte and coronary microvascular growth in a well controlled experimental load model. The overarching hypothesis of the proposal is that fetal heart growth is exquisitely sensitive to hemodynamic load and that altered growth leads to irreversible changes in cardiac myocyte and coronary vascular function for life. The proposed experiments will demonstrate for the first time the precise responses that determine how the fetal heart adapts to changes in loading conditions during late gestation when all the terminal maturation processes are underway. Completion of the proposed work will provide a clearer understanding of the relationship between fetal cardiomyocyte and coronary vascular growth, how this interrelationship affects fetal cardiac function, which changes persist into adulthood and how adult heart function is affected. This work is an essential step in understanding the mechanisms responsible for the association between fetal growth restriction and adult cardiovascular disease.

心血管疾病是发达国家的首要死因。流行病学研究有 表明产前时期对终生健康的深远重要性。对此的可能解释 关系是，胎儿晚期是一个生长旺盛的时期，决定了心肌细胞的数量 以及终生冠状血管的结构。不利的宫内条件导致胎儿生长 限制会改变心脏负荷并损害心脏生长。而成人心脏的适应能力 心血管疾病是有限的，胎儿心脏具有高度可塑性，正在快速适应以最好地满足 宫内情况。胎儿心肌细胞的数量和胎儿的解剖尺寸 冠状动脉循环不是固定的，而是可以根据产前条件而上下改变。很遗憾， 胎儿对次优宫内环境的反应可能不会给胎儿带来有利的结果或 到了成年以后。不可能理解子宫内生长迟缓的破坏性影响 除非我们刻意研究心肌细胞和冠状动脉微血管的生长，否则对胎儿心肌的影响 良好控制的实验负载模型。 该提案的总体假设是胎儿心脏的生长对以下因素极其敏感： 血流动力学负荷和生长改变会导致心肌细胞和冠状动脉发生不可逆的变化 终生血管功能。拟议的实验将首次证明精确的响应 决定胎儿心脏如何适应妊娠晚期负荷条件的变化，此时所有的 最终成熟过程正在进行中。 完成拟议的工作将使人们更清楚地了解胎儿之间的关系 心肌细胞和冠状血管生长，这种相互关系如何影响胎儿心脏功能， 变化持续到成年期以及成人心脏功能如何受到影响。这项工作是重要的一步 了解胎儿生长受限与成人之间关联的机制 心血管疾病。