Blood Flow Regulation of Pharyngeal Arch Artery Morphogenesis

早期胚胎心脏流出物通过对称的一对称为咽弓动脉的血管输送。这个血管歧管重塑成部分肺动脉、主动脉和其他重要的大血管。许多儿童患有严重的出生缺陷，其根源在于血管网络的重组方式，如果不进行复杂的手术干预，可能会立即危及生命。很少有基因被发现控制这些过程，这表明来自血液流动的机械力影响局部细胞信号以控制血管生长和形状变化。确定咽弓动脉生长是如何被控制的是理解心脏形成和潜在帮助心脏再生的关键基础科学需要。该研究结合了新颖的计算和实验方法，定量模拟和直接操纵发育中的咽弓动脉的流体力分布，并预测这些变化如何指导下游血管网络重塑和血管壁成熟。本研究旨在提供一种诊断和纠正出生前大血管畸形的新策略。该项目将推进血流动力学如何控制胚胎咽部弓动脉网络的多尺度重塑的基础知识，咽部弓动脉网络是心脏流出道和大血管的前体。这项新技术能够实现活体胚胎中单个网络血管的无创可视化和闭塞，并结合了反映生理边界条件的集总参数边界条件的计算流体动力学模拟。本项目将测试咽弓动脉网络中保守的血流动力学特征控制其局部重塑和成熟的总体假设。体内咽弓动脉光闭塞引起的急性血流动力学改变与下游血管网络管腔生长和重塑有关。然后，这些流体力将与局部血管壁厚度、组成和表型的时间变化相关。最后，直接光消融闭塞的咽弓动脉将用于恢复血流动力学信号，并测试这是否恢复谱系模式，和/或下游血管重塑。通过分析来自多个实验的实际解剖结构，而不是使用单一的共识几何结构，将产生关于细胞组成和/或流场局部偏差的形态发生结果变异性的关键信息，以及它们对血液动力学信号急性变化的耐受性。

Early embryonic heart outflow is delivered via symmetric pairs of vessels called the pharyngeal arch arteries. This vascular manifold remodels into portions of the pulmonary arteries, aorta, and other critical great vessels. Many children suffer from serious birth defects that have their origin in how this vascular network reorganizes, and can be immediately life threatening without complex surgical intervention. Few genes have been found that control these processes, suggesting that mechanical forces from blood flow influence local cellular signaling to control vessel growth and shape changes. Determining how pharyngeal arch artery growth is controlled is a key basic science need for understanding heart formation and potentially to help with heart regeneration. The research integrates novel computational and experimental approaches to quantitatively model and directly manipulate the profile of fluid forces in the developing pharyngeal arch arteries, and predict how these changes direct downstream vascular network remodeling and the maturation of the vascular walls. The research is targeted at producing a new strategy to diagnose and correct great vessel malformations before birth.This project will advance fundamental knowledge of how hemodynamic forces control multiscale remodeling of the embryonic pharyngeal arch artery network, the precursors to the cardiac outflow tract and great vessels. Novel technology enabling noninvasive visualization and occlusion of individual network vessels in live embryos is combined with computational fluid dynamics simulations that incorporate lumped parameter boundary conditions reflecting physiological boundary conditions. This project will test the overall hypothesis that conserved hemodynamic signatures within the pharyngeal arch artery network controls its local remodeling and maturation. Acute hemodynamic changes resulting from in vivo pharyngeal arch artery photo-occlusion will be correlated with downstream vascular network lumen growth and remodeling. These fluid forces will then be correlated with temporal changes in local vascular wall thickness, composition and phenotype. Finally, direct photo-ablation of occluded pharyngeal arch arteries will be used to restore hemodynamic signaling, and test whether this restores lineage patterning, and/or downstream vascular remodeling. By analyzing actual anatomy from multiple experiments rather than using a single consensus geometry, key information will be generated regarding the variability of morphogenic outcomes to local deviations in cellular composition and/or flow fields, and further their tolerance to acute changes in hemodynamic signaling.