Mechanotransduction and transcriptional regulation during artery development

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ABSTRACT Ischemic heart disease resulting from pathology of the coronary arteries is the leading cause of death. One potential therapy could be medically stimulating artery regeneration in diseased hearts, yet this remains a distant goal. One roadblock to progress is that the mechanisms of coronary artery development are still largely unknown. This proposal uses a novel stem cell-to- endothelial cell differentiation protocol that enables new and more precise approaches to discover arterialization factors. Our previous research identified the transcription factor Dach1 as a critical component of coronary artery differentiation and morphogenesis. One outstanding follow-up question to this research is what are the genes induced by Dach1 that influence artery endothelial cell differentiation. Identifying these has been slow and difficult owning to inadequate endothelial cell culture models that can be used to quickly interrogate multiple genes. Our colleagues, in collaboration with our lab, have recently published a highly efficient and easy to execute stem cell-to-artery endothelial cell differentiation that recapitulates steps in early human development We will use this model to: 1. Investigate the mechanisms underlying Dach1-induced artery differentiation and 2. Investigate whether shear stress influences artery endothelial cell differentiation. This data will illuminate mechanistically how Dach1 induces arterial differentiation. Additionally, we will integrate the effects of shear stress on the ability of human cells to differentiate into artery and veins cells. Understanding these signaling pathways could identify novel therapeutic targets aimed at enhancing revascularization of diseased hearts through expanding artery networks.