Mechanotransduction and transcriptional regulation during artery development

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PROJECT SUMMARY Heart disease, the most common cause of death, frequently arises from blocking blood flow to cardiac muscle. Blood flow travels to the heart first through coronary arteries and then into a capillary network where oxygen exchange occurs. One approach to treating heart disease has been to expand the capillary network, but this has achieved limited success. Here, we propose to instead expand coronary artery networks and promote the development of collateral arteries, which are a subtype of artery with the potential to form a natural bypass. In the previous funding period, our laboratory discovered cellular and molecular mechanisms driving coronary artery formation in the developing embryo, including how the transcription factor Dach1 supports artery growth through regulating blood flow stimulated cell behaviors (Chang, 2017, Genes and Dev). We also described how the chemokine CXCL12 triggers collateral artery formation in the injured heart during the neonatal growth period (Das, 2019, Cell). We hypothesize that these developmental pathways can be utilized to stimulate adult coronary artery regeneration and provide beneficial outcomes during cardiac injury and disease. Preliminary studies activating Dach1 or CXCl12 in adults shows indications of enhanced recovery following experimental myocardial infarction. We will use the following Aims to further explore their reparative potential. Aim 1 will use tissue clearing, whole organ imaging technology, and computational modeling to define how injury, Dach1 overexpression, and CXCL12 administration alter artery structure and affect blood flow parameters. Aim 2 will use cardiac injury models to intensively study how Dach1- and CXCL12-induced artery growth and collateral development enhance recovery post-myocardial infarction. Aim 3 will delve into the mechanisms by which Dach1 stimulates artery endothelial cell differentiation and morphogenesis. This work is significant because delineating how developmental signals stimulate coronary artery regeneration could ultimately contribute to therapeutic interventions for heart disease. The work is innovative because it takes a new approach to revascularization—targeting artery differentiation rather than just the microvasculature. It also further develops cutting edge experimental techniques such as adult whole organ imaging and a novel in vitro endothelial cell differentiation model, which could ultimately benefit the cardiovascular research community at large. Finally, successful completion of the Aims is ensured by the interdisciplinary environment at Stanford University and collaborative track record between this group of investigators (Drs. Kristy Red-Horse, Kyle Loh, Alison Marsden, and Daniel Bernstein). The proposed work will enhance our knowledge on cardiovascular development and regeneration by illuminating the biology of the hitherto-enigmatic collateral arteries, as well as how transcriptional regulators such as DACH1 determine artery fate.