Regulation of Fetal Myocyte Development

描述（由申请人提供）：完整的肾素-血管紧张素系统并非导致成人负荷诱导的心脏肥大的专性因素，尽管血管紧张素II在心肌重塑中起重要作用。胎儿心脏对负荷增加的反应和心脏生长中肾素-血管紧张素系统的作用知之甚少。在人类和绵羊等物种中，大多数心肌细胞在出生时就已终末分化，心脏的出生后生长是通过肥大而不是通过增加细胞数量来实现的。因此，需要确定影响心肌内存在的肌细胞总数的因素。子宫内事件加速心肌细胞的终末分化速率或增加细胞死亡（凋亡）速率将导致心肌细胞总数减少。该建议旨在研究正常和病理状态（慢性胎儿贫血诱导的容量超负荷）下血管紧张素II在胎儿发育的两个阶段中调节心肌细胞生长、成熟和增殖的作用。具体而言，我们打算使用长期插管的胎羊模型来研究（1）体内心脏负荷增加时调节胎儿心肌细胞肥大、增生和凋亡的机制;（2）选择性血管紧张素II受体阻断剂对这些反应的不同影响;（3）这些干预是否会导致心脏形态和功能的永久性改变。子宫内心肌细胞生长、成熟和增殖的适应性变化可能导致心脏形态和功能的改变，最终可能导致心脏在成年期患心血管疾病和心室功能改变。

DESCRIPTION (provided by applicant): An intact renin-angiotensin system is not obligate for the development of load-induced cardiac hypertrophy in the adult, although ANG II plays an important role in myocardial remodeling. The response of the fetal heart to increased load and the role of the renin-angiotensin system in cardiac growth are poorly understood. In species like the human and sheep, most cardiomyocytes are terminally differentiated at birth, with postnatal growth of the heart occurring by hypertrophy and not by increasing cell number. Thus factors affecting the total number of myocytes present within the myocardium need to be identified. Intrauterine events that accelerate the rate of terminal differentiation of cardiomyocytes or increases the rate of cell death (apoptosis) will lead to a reduction in the total cardiomyocyte number. This proposal is designed to investigate in normal and pathological states (chronic fetal anemia induced volume overload) the role of angiotensin II in regulating growth, maturation and proliferation of cardiac myocytes during two stages of fetal development. Specifically, we intend to use a chronically-catheterized fetal sheep model to investigate (1) mechanisms regulating fetal cardiomyocyte hypertrophy, hyperplasia and apoptosis in responses to increased cardiac load in vivo; (2) the differential effects of selective angiotensin II receptor blockade on these responses and, (3) whether these interventions produce permanent alterations in cardiac morphology and function. Adaptive changes in cardiomyocyte growth, maturation and proliferation in utero could produce alterations in cardiac morphology and function that may ultimately program the heart for cardiovascular disease and ventricular function in adult life.