Regulation of Fetal Cardiac Growth After Correction of Increased Hemodynamic Load

描述（由申请人提供）：拟议项目的目的是确定胎儿心脏生长的机制是如何通过长时间增加的心血管容量或压力负荷的恢复而改变的。胎儿心脏通过改变其正常生长模式来非常敏感地适应血流动力学负荷条件的改变。在正常生长过程中，胎儿经历了广泛的心肌细胞增殖（在终末分化之前）和心肌细胞扩大。胎儿治疗的可能性提出了胎儿心脏如何在血流动力学负荷条件改变后恢复的问题。体积负荷的增加和压力负荷的增加都会增加心脏与体重的比率，但从这些情况中恢复可能是不同的。目的1：当胎儿心脏/体重在短暂的心肌细胞增殖加速后恢复正常时，心肌内的肌细胞数量是正常的。我们的发现支持了这一假设，即贫血胎儿肥厚心脏的肌细胞并不大。恢复后，胎儿心脏将包含正常数量的肌细胞。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，心肌内的肌细胞数量减少。我们发现高血压诱导心肌细胞增大，这一假设得到了支持。在恢复之后，胎儿心脏将因此包含较少数量的肌细胞。目的3：胎儿心脏在压力负荷后的恢复期，细胞凋亡和与细胞凋亡相关的信号通路被激活，而不是体积负荷。体积负荷（由于贫血）不会增加动脉压力，因此体积负荷的校正不会改变收缩壁应力，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心室曲率半径和增加壁厚来使壁应力正常化。卸荷后，心室壁应力下降并诱导细胞凋亡。胎儿具有显著的生长和适应能力。许多婴儿在出生前就能更好地忍受先天性心血管疾病。我们正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治疗最有效。

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.