Department of Biomedical Engineering, Carnegie Mellon University, 700 Technology Drive, Pittsburgh, PA 15219, USA.
Biomech Model Mechanobiol. 2012 Sep;11(7):1057-73. doi: 10.1007/s10237-012-0373-z. Epub 2012 Feb 4.
In the early embryo, a series of symmetric, paired vessels, the aortic arches, surround the foregut and distribute cardiac output to the growing embryo and fetus. During embryonic development, the arch vessels undergo large-scale asymmetric morphogenesis to form species-specific adult great vessel patterns. These transformations occur within a dynamic biomechanical environment, which can play an important role in the development of normal arch configurations or the aberrant arch morphologies associated with congenital cardiac defects. Arrested migration and rotation of the embryonic outflow tract during late stages of cardiac looping has been shown to produce both outflow tract and several arch abnormalities. Here, we investigate how changes in flow distribution due to a perturbation in the angular orientation of the embryonic outflow tract impact the morphogenesis and growth of the aortic arches. Using a combination of in vivo arch morphometry with fluorescent dye injection and hemodynamics-driven bioengineering optimization-based vascular growth modeling, we demonstrate that outflow tract orientation significantly changes during development and that the associated changes in hemodynamic load can dramatically influence downstream aortic arch patterning. Optimization reveals that balancing energy expenditure with diffusive capacity leads to multiple arch vessel patterns as seen in the embryo, while minimizing energy alone led to the single arch configuration seen in the mature arch of aorta. Our model further shows the critical importance of the orientation of the outflow tract in dictating morphogenesis to the adult single arch and accurately predicts arch IV as the dominant mature arch of aorta. These results support the hypothesis that abnormal positioning of the outflow tract during early cardiac morphogenesis may lead to congenital defects of the great vessels due to altered hemodynamic loading.
在胚胎早期，一系列对称的、成对的血管，即主动脉弓，环绕着前肠，并将心输出量分配给不断生长的胚胎和胎儿。在胚胎发育过程中，弓状血管经历了大规模的非对称形态发生，形成了具有物种特异性的成人大血管模式。这些转变发生在一个动态的生物力学环境中，它可以在正常弓状结构的发育或与先天性心脏缺陷相关的异常弓状形态中发挥重要作用。在心脏环形成的后期，流出道的迁移和旋转停滞已经被证明会导致流出道和几个弓状异常。在这里，我们研究了由于胚胎流出道角度方向的扰动而导致的血流分布变化如何影响主动脉弓的形态发生和生长。我们通过将体内弓状形态测量与荧光染料注射和血流驱动的基于生物工程优化的血管生长建模相结合，证明了流出道方向在发育过程中会发生显著变化，并且相关的血流负荷变化可以极大地影响下游主动脉弓的模式形成。优化结果表明，通过平衡能量消耗和扩散能力，可以产生与胚胎中所见的多种弓状血管模式，而仅最小化能量则会导致成熟主动脉弓中的单一弓状结构。我们的模型进一步表明，流出道的方向在决定成人单弓的形态发生方面起着至关重要的作用，并准确预测了弓 IV 是主动脉的主导成熟弓。这些结果支持了这样一种假设，即在早期心脏形态发生过程中，流出道的异常定位可能会由于血流负荷的改变而导致大血管的先天性缺陷。
