Blood Flow Regulation of Pharyngeal Arch Artery Morphogenesis

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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.