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: 8521755
• 负责人: GEORGE D GIRAUD
• 金额: $ 16.73万
• 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/8521755
• 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死亡的主要原因。流行病学研究已有 表明产前时期对终身健康的重要性非常重要。可能的解释 关系是胎儿后期的生长时期决定了心肌细胞的数量 以及生命的冠状动脉脉管系统的结构。宫内不良条件导致胎儿生长 限制会改变心脏负荷并损害心脏的生长。而成人心脏适应的能力 心血管疾病有限，胎儿心脏是高度塑料的，经过快速适应以最佳满足 宫内条件。胎儿心肌细胞的数量和胎儿的解剖学维度 冠状动脉循环不是固定的，但可以通过产前条件上下改变。很遗憾， 胎儿对亚最佳子宫内环境的反应可能不会导致胎儿或 后来在成年人中。不可能了解宫内生长迟滞的毁灭性影响 在胎儿心肌上，除非我们故意研究心肌细胞和冠状动脉微血管生长 控制良好的实验负载模型。 该提案的总体假设是胎儿心脏的生长对 血液动力学负荷和生长改变会导致心肌细胞和冠状动脉的不可逆转变化 生命的血管功能。提出的实验将首次证明精确的响应 这决定了胎儿心脏在妊娠后期如何适应加载状况的变化 终端成熟过程正在进行中。 拟议工作的完成将对胎儿之间的关系有更清晰的了解 心肌细胞和冠状动脉血管生长，这种相互关系如何影响胎儿心脏功能 变化持续到成年，以及成人心脏功能的影响。这项工作是重要的一步 了解负责胎儿生长限制与成人之间关联的机制 心血管疾病。