The complex valves and walls of the heart’s pulmonary and aortic outlets begin as a much simpler structure, a singular tubular outflow tract. Proper growth, remodeling, and maturation of the outflow tract during fetal development are essential for delivering oxygenated circulation after birth. Defects in the sizes and shapes of the pulmonary and aortic outlets are responsible for many forms of congenital heart disease and contribute to a large portion of preterm fetal deaths. Investigations of the genetics that initiate outflow tract development have yet to explain the remodeling and maturation of its tissues into valves and other mature structures.

Jonathan T. Butcher, Biomedical Engineering, is leading a multidisciplinary research team that is investigating the role of mechanical forces in the growth, remodeling, and maturation of the cardiac outflow tract. Mechanical forces—such as shear stress, pressure, and tension—are ever-present during embryonic heart development. These forces may orchestrate local cellular decisions that govern outflow tract remodeling, but genetic analyses can provide only limited insight into the role that mechanical forces play. This research will apply innovative research techniques, dynamic spatial nucleotide sequencing, quantitative live imaging, and state-of-the-art computational analysis to investigate how mechanical forces drive cellular- to tissue-level responses during outflow tract morphogenesis.

This research will substantially advance our understanding of the role of mechanical forces in embryonic heart development—particularly how mechanical forces participate in the molecular regulation and conditional signaling that govern outflow tract growth, remodeling, and maturation. The findings could inform strategies for manipulating such signaling programs to reduce the severity of coronary heart disease in utero, prior to birth.

NIH Award Number: 1R01HL160028-01A1