Regulation of Fetal Cardiac Growth After Correction of Increased Hemodynamic Load

描述(由申请人提供)：拟议项目的目标是确定胎儿心脏发育的机制如何通过从心血管容量或压力负荷增加的较长时期恢复而改变。胎儿心脏通过改变其正常的生长模式来非常敏感地适应血流动力学负荷条件的变化。在正常生长期间，胎儿经历广泛的心肌细胞增殖(在终末分化之前)以及心肌细胞的增大。胎儿治疗的可能性提出了一个问题，即在血流动力学负荷改变的情况得到纠正后，胎儿心脏如何恢复。增加容量负荷和增加压力负荷都会增加心脏与体重的比率，但从这两种情况下恢复可能是不同的。目的1：当胎儿心脏/体重在短暂的心肌细胞加速增殖后恢复正常时，心肌内的心肌细胞数量是正常的。这一假设得到了我们的发现的支持，即贫血胎儿肥厚的心脏中的心肌细胞并不大。因此，在恢复后，胎儿心脏将包含正常数量的心肌细胞。目的2：当胎儿心脏/体重在短暂的心肌细胞加速增大后恢复正常时，心肌内的心肌细胞数量减少。我们的发现支持这一假说，即高血压会导致心肌细胞增大。因此，在复苏后，胎儿心脏中的心肌细胞数量将会减少。目的：在压力负荷后的恢复期，胎儿心脏中的细胞凋亡和与细胞凋亡相关的信号通路被激活，而不是容量负荷。容量负荷(由于贫血)不会增加动脉压，因此校正容量负荷不会改变收缩期壁应力，也不会强烈刺激细胞凋亡。相反，在高血压期间，胎儿心脏会通过减小室曲率半径和增加室壁厚度来使室壁应力正常化。卸载后，室壁应力会下降，并诱导细胞凋亡。胎儿具有非凡的生长和适应能力。许多婴儿在出生前对先天性心血管疾病的耐受性更好。我们正在试图了解胎儿的心脏是如何从这种情况中恢复的。这将帮助我们知道什么时候胎儿疗法会起到最大的作用。

DESCRIPTION (provided by applicant): The objective of the proposed project is to determine how the mechanisms of fetal cardiac growth are altered by recovery from an extended period of increased cardiovascular volume or pressure load. The fetal heart very sensitively adjusts to alterations in hemodynamic loading conditions by modifying its normal growth patterns. During normal growth, the fetus undergoes extensive cardiomyocyte proliferation (prior to terminal differentiation) as well as cardiomyocyte enlargement. The possibility of fetal therapies raises the question of how the fetal heart recovers after correction of altered hemodynamic loading conditions. Increased volume load and increased pressure load both increase the ratio of the heart to body weight, but recovery from these conditions may be different. Aim 1: When the fetal heart/body weight normalizes following a transient period of accelerated cardiomyocyte proliferation, the number of myocytes within the myocardium is normal. This hypothesis is supported by our finding that myocytes are not larger in hypertrophied hearts of anemic fetuses. Following recovery, the fetal heart will therefore contain a normal number of myocytes. Aim 2: When the fetal heart/body weight normalizes following a transient period of accelerated cardiomyocyte enlargement, the number of myocytes within the myocardium is reduced. This hypothesis is supported by our finding that hypertension induces cardiomyocyte enlargement. Following recovery, the fetal heart will therefore contain a fewer number of myocytes. Aim 3: Apoptosis and signaling pathways associated with apoptosis are activated in the fetal heart in the recovery period following a pressure load, but not a volume load. Volume load (due to anemia) does not increase arterial pressures, therefore correction of volume load will not change systolic wall stress and apoptosis will not be strongly stimulated. In contrast, during hypertension the fetal heart will normalize wall stress by reducing the ventricular radius of curvature and increasing wall thickness. Upon unloading, ventricular wall stress will fall and induce apoptosis. Fetuses have a remarkable capacity for growth and adaptation. Many babies tolerate congenital cardiovascular diseases better before they are born. We are trying to learn how the hearts of fetuses recover from such conditions. This will help us know when fetal therapies will do the most good.