Regulation of Fetal Myocyte Development

描述(申请人提供)：完整的肾素-血管紧张素系统不是成人负荷性心肌肥厚发生的必要条件，尽管Ang II在心肌重塑中起重要作用。胎儿心脏对负荷增加的反应以及肾素-血管紧张素系统在心脏生长中的作用还知之甚少。在像人类和绵羊这样的物种中，大多数心肌细胞在出生时就已经分化为终末，出生后心脏的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心肌细胞总数的因素。加速心肌细胞终末分化或增加细胞死亡(细胞凋亡)的宫内事件将导致心肌细胞总数的减少。本研究旨在探讨血管紧张素II在正常和病理状态下(慢性胎儿贫血引起的容量超负荷)在胎儿发育的两个阶段中对心肌细胞生长、成熟和增殖的调节作用。具体地说，我们打算使用一个长期置管的胎羊模型来研究(1)在活体心脏负荷增加时调节胎儿心肌细胞肥大、增殖和凋亡的机制；(2)选择性血管紧张素II受体阻滞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会导致心脏形态和功能的变化，最终可能会在成年后为心血管疾病和心脏功能设定程序。

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.