Mechanisms of Fetal Myocardial and Coronary Growth Synchrony

描述(由申请人提供)：该实验室的长期目标是通过发现心脏发育的调节机制来改善胎儿、新生儿和成人的心脏健康。流行病学研究将成人冠心病的发展与胎儿期的事件联系起来。胎儿期心肌细胞和冠状动脉生长的关系最终决定了最大冠状动脉储备，这是成人的一个重要危险因素。胎儿心肌耗氧量改变是正常心脏的常见因素，在胎盘功能不全、胎儿缺氧、增加心脏工作的先天性畸形和胎儿贫血的情况下也是如此。在子宫内使冠状动脉生长与心肌细胞生长同步的驱动因素可能是氧，但氧水平可能为冠状动脉重塑提供刺激的潜在机制尚不清楚。解决我们知识中的这一差距将使我们能够开发出诊断和纠正心肌细胞-毛细血管不匹配的策略，这种不匹配可能是疾病易感性的基础。我们认为，短暂的供氧量与需氧量的周期性不匹配提供了将胎儿冠状动脉血管生长与心肌细胞生长联系起来的信号。我们已经建立了一个工作模型，通过特定的化学信号将冠状动脉与心肌细胞的生长联系起来，由此我们提出了以下具体目标：1)确定心肌氧需求对胎儿冠状动脉血管生长的调节程度。2)确定心肌耗氧量增加时腺苷信号对胎儿冠脉生长的调节程度。3)确定慢性增加的氧需量如何通过调节途径成分来增强腺苷和血管内皮生长因子信号。这些目标将在慢性仪器化的胎羊模型中进行测试，在该模型中，通过创新地应用线粒体解偶联剂来增加心脏需氧量。为了确定腺苷信号在冠状动脉生长适应过程中的重要性，在该模型中还将使用腺苷受体拮抗剂。冠状动脉储备将被用来测试体内冠状动脉的生长，而形态测量技术将被用来精确地量化特定血管床的变化。分子和酶分析将被用来确定关键途径是如何调控胎儿冠状动脉生长的。了解心肌耗氧量作为胎儿冠状动脉血管生长的决定因素的作用，将有助于认识和治疗将影响冠状动脉血流储备和心血管健康终身的胎儿状况。

DESCRIPTION (provided by applicant): The broad, long-term objective of this laboratory is to improve fetal, neonatal and adult cardiac health by discovering the mechanisms regulating cardiac development. Epidemiological research links the adult development of coronary heart disease to events in the fetal period. The relationship between cardiomyocyte and coronary growth in the fetal period ultimately determines maximal coronary reserve, an important risk factor in the adult. Altered fetal myocardial oxygen demand is a common element in normal hearts as it is in conditions of placental insufficiency, fetal hypoxia, congenital malformations that increase cardiac work, and fetal anemia. The driving stimulus synchronizing coronary growth to cardiomyocyte growth in utero is likely to be oxygen, but the underlying mechanisms by which oxygen levels might provide a stimulus for coronary remodeling is not known. Solving this gap in our knowledge would enable us to develop strategies for diagnosing and correcting the cardiomyocyte-capillary mismatch that may underlie vulnerability for disease. We propose that brief periodic mismatches in oxygen demand vs. supply provide signals that link fetal coronary vascular growth to cardiomyocyte growth. We have developed a working model that links coronary to cardiomyocyte growth through specific chemical signals, from which we propose the following specific aims: 1) Determine the degree to which myocardial oxygen demand regulates fetal coronary vascular growth. 2) Determine the degree to which adenosine signaling regulates fetal coronary growth during increased myocardial oxygen demand. 3) Determine how chronically increased oxygen demand potentiates adenosine and VEGF signaling by regulation of pathway components. These aims will be tested in a chronically instrumented fetal sheep model in which cardiac oxygen demand is increased by the innovative application of a mitochondrial uncoupling agent. In order to determine the importance of adenosine signaling for the adaptive process of coronary growth, and adenosine receptor antagonist will also be employed in this model. Coronary reserve will be used to test for coronary growth in vivo, while morphometric techniques will be used to precisely quantify changes in specific vessel beds. Molecular and enzyme assays will be called upon to determine how critical pathways are regulating fetal coronary growth. Understanding the role of myocardial oxygen demand as a determinant of fetal coronary vascular growth will lead to recognition and treatment of fetal conditions that will impact coronary flow reserve and cardiovascular health for life.