ANGIOTENSIN REGULATES HEART GROWTH IN UTERO

由于哺乳动物在出生时心肌细胞的数量是固定的， 包括人类在内的物种，子宫内的心脏生长也决定了 在新生儿，青年，甚至成人的后续增长的潜力。 因此，子宫内流入或流出道阻塞引起的小腔室可能 出生后无法正常发育。 同样，成年人对 瓣膜或缺血性疾病可能受到子宫内事件的限制。 的 子宫内心脏生长和终末分化的调控机制 并不完全理解。 血管紧张素II和血流动力学负荷，收缩压和 舒张期，是心脏生长的假定关键决定因素， 子宫内分化 此外，Ang II很可能是一个 子宫内血流动力学负荷重要调节器。 因此，血管紧张素可 直接（受体介导）和间接（负载介导）影响 心脏生长和分化。 本建议的目的是 分离这些贡献并理解所涉及的机制。 将使用长期内固定的胎羊，以便 血管紧张素血液动力学负荷和直接作用可以得到控制， 明确各自的作用。 收缩压负荷将是 通过主动脉封堵器置于左心室。 血管紧张素会 用AT 1或2拮抗剂阻断。 血流动力学负荷的影响 存在零、基线或增加的Ang Ii局部直接激动， 测定 同样，基线、无或增加的Ang II的作用 在未负荷的动物中评估局部激动作用。 心脏生长和 将通过大体和显微镜测定来评估分化， 双核率。 RAS组分的基因表达将用于 评估肌细胞成熟。 血管紧张素对MAP激酶的影响 将评估通路激活以确定 分化和增殖。 该项目将提供明确的 关于血管紧张素II在调节胎儿心脏生长中的作用的数据 因此是本计划项目补助金的组成部分。

Since the number of myocytes is fixed near the time of birth in mammalian species including humans, heart growth in utero also determines the potential for subsequent growth in the neonate, youth, and even adult. Thus, small chambers caused by inflow or outflow obstruction in utero may be unable to grow adequately after birth. Likewise, adult responses to valvular or ischemic disease may be limited by events in utero. The mechanisms regulating cardiac growth and terminal differentiation in utero are incompletely understood. Ang II and hemodynamic load, systolic and diastolic, are putative key determinants of cardiac growth and differentiation in utero. Furthermore, Ang II is likely to be an important regulator of hemodynamic load in utero. Thus, angiotensin may have direct (receptor mediated) and indirect (load mediated) effects on cardiac growth and differentiation. it is the purpose of this proposal to separate these contributions and to understand the mechanisms involved. Chronically instrumented fetal sheep will be utilized in order that hemodynamic load and direct action of angiotensin can be controlled and their respective roles definitively defined. A systolic load will be placed on the left ventricle by aortic occluder. Angiotensin will be blocked with AT 1 or 2 antagonists. The effects of hemodynamic load with zero, baseline or increased Ang Ii local direct agonism present are determined. likewise, the effect of baseline, no, or increased Ang II local agonism will be assessed in unloaded animals. Cardiac growth and differentiation will be assessed by gross and microscopic mensuration and percent binucleation. Gene expression of RAS components will be used to assess myocyte maturation. The effect of angiotensin on MAP kinase pathway activation will be assessed to determine a mechanism for differentiation and proliferation. This project will provide definitive data regarding the role of Ang Ii in the regulation of fetal heart growth and thus is an integral part of this Program Project Grant.