Regulation of Fetal Myocyte Development

描述（由申请人提供）：尽管ANG II在心肌重塑中起重要作用，但完整的肾素-血管紧张素系统并不是成人负荷性心脏肥厚的必要条件。胎儿心脏对增加负荷的反应和肾素-血管紧张素系统在心脏生长中的作用尚不清楚。在人类和绵羊等物种中，大多数心肌细胞在出生时终末分化，出生后心脏的生长发生在肥大而不是细胞数量的增加。因此，需要确定影响心肌细胞总数的因素。加速心肌细胞终末分化速率或增加细胞死亡（凋亡）速率的宫内事件将导致心肌细胞总数减少。本研究旨在探讨在正常和病理状态下（慢性胎儿贫血诱导的容量过载），血管紧张素II在胎儿发育两个阶段调节心肌细胞生长、成熟和增殖中的作用。具体来说，我们打算使用一个长期插管的胎羊模型来研究：(1)在体内对心脏负荷增加的反应中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受体阻断对这些反应的不同影响；(3)这些干预是否会对心脏形态和功能产生永久性改变。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后发生心血管疾病和心室功能。

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.