Quantification of vascular morphogenesis in the chick embryo and its relationship to the hemodynamic environment.

摘要

Congenital heart disease (CHD) has the highest incidence and mortality rate of all birth defects in the U.S., occurring in at least 8 of every 1000 live births, and accounting for more than 24% of birth defect related infant deaths. Clinical and experimental data indicate that the hemodynamic environment has a significant role in the etiology of CHD, motivating the development of fetal valvuloplasty to reverse the progression of heart defects in utero. The efficacy of this intervention relies heavily on understanding the biomechanical relationships between blood flow and cardiovascular growth and remodeling. This thesis describes several studies using the chick embryo model designed to quantify vascular morphogenesis in vivo and link the observed trends to hemodynamic forces such as wall shear stress (WSS). Morphogenesis of the embryonic aortic arches, a series of bilaterally paired vessels surrounding the foregut and the precursors to the great vessels, was investigated using fluorescent dye injection and optical coherence tomography imaging. These experimental results were combined with computational fluid dynamics models of flow through the aortic arches, which revealed a correlation between transitioning aortic arch patterns and acute increases in WSS. Additionally, a regression analysis found a strong polynomial relationship between luminal aortic arch growth and deviations in WSS. Transformations of the aortic arches were further investigated using a computational optimization-based growth model. The model demonstrated that selection of the adult single aortic arch was influenced by the rotation of the outflow tract of the heart. The principle of minimum work, combined with this model, accurately predicted the transformation to a single aortic arch configuration. In order to support predictive computational models, quantitative data of vascular growth is required. Morphogenesis of an embryonic vitelline artery was tracked using a time-lapse, long-term optical coherence tomography based imaging system. Global and local growth of the artery was quantitatively analyzed at high spatial and temporal resolution. Finally, a model of hypoplastic left heart syndrome in the chick embryo was used to determine alterations in intracardiac flow patterns that may lead to the progression of this defect. Out of three venous injection sites, two shifted their flow pattern significantly. This change was observed soon after the intervention to generate the defect was performed, suggesting that flow disruption is an early insult leading to hypoplastic left heart syndrome. Together, these studies support the importance of the hemodynamic environment in determining vascular morphogenesis in the embryo. The combined experimental and computational approach provided new quantitative data of embryonic vascular morphogenesis. The results of these studies and the methods established in this thesis lay the foundation for future research on the biomechanics of cardiovascular development.