Globally 1 in 100 children are born with significant congenital heart defects (CHD), representing either new genetic mutations or epigenetic insults that alter cardiac morphogenesis in utero. Embryonic CV systems dynamically regulate structure and function over very short time periods throughout morphogenesis and that biomechanical loading conditions within the heart and great-vessels alter morphogenesis and gene expression. This proposal has structured around a common goal of developing a comprehensive and predictive understanding of the biomechanics and regulation of great-vessel development and its plasticity in response to clinically relevant epigenetic changes in loading conditions. Biomechanical regulation of vascular morphogenesis, including potential aortic arch (AA) reversibility or plasticity after epigenetic events relevant to human CHD are investigated using multimodal experiments in the chick embryo that investigate normal AA growth and remodeling, microsurgical instrumentation that alter ventricular and vascular blood flow loading during critical periods in AA morphogenesis. WP 1 establishes our novel optimization framework, incorporates basic input/output in vivo data sets, and validates. In WP 2 and 3 the numerical models for perturbed biomechanical environment and incorporate new objective functions that have in vivo structural data inputs and predict changes in structure and function. WP 4 incorporates candidate genes and pathways during normal and experimentally altered AA morphogenesis. This proposal develops and validates the first in vivo morphomechanics-integrated three-dimensional mathematical models of AA growth and remodeling that can predict normal growth patterns and abnormal vascular adaptations common in CHD. Multidisciplinary application of bioengineering principles to CHD is likely to provide novel insights and paradigms towards our long-term goal of optimizing CHD interventions, outcomes, and the potential for preventive strategies.