Executive Summary : | Artery Reassembly is an artery endothelial cell (EC) driven process which builds coronary collateral arteries de novo. Artery Reassembly is a four-step process which includes migration, de-differentiation, proliferation and coalescence of artery ECs into new collateral artery segments. Proliferating artery ECs promote Artery Reassembly and further cardiac function by improving stroke volume and cardiac output in mice. A recent study from our group shows that this presumably differentiated cardiac cell type- artery EC, is able to de-differentiate in response to cardiac injury. De-differentiation of artery cells is conjugated with their ability to re-enter cell cycle and facilitation of collateral artery formation by Artery Reassembly. Thus, determining the cell cycle status of artery ECs through each step of Artery reassembly and examining candidate molecular drivers of artery EC proliferation, can help us strategize ways to improve Artery Reassembly and consequent collateral artery formation and cardiac regeneration. In this proposal we are investigating the process of cell cycle re-entry of terminally differentiated artery EC, in response to coronary artery occlusion. Using rigorous mouse genetics experiments, sophisticated lineage tracing techniques and whole heart imaging at single cell resolution, we intend to ask questions which will significantly enhance our current understanding of how, when and why a given cell determines whether to keep or change its identity. With the completion of this proposal we will know: how is cell cycle re-entry of artery ECs coordinated across space and time in response to injury (aim 1)?, can we modulate this cellular process to enhance Artery Reassembly in non-regenerative hearts, and hence improve their cardiac function over time (aim 2)?, and finally, does Wnt-Fzd4 activity in artery endothelial cells regulate the proliferation status of artery cells in response to myocardial injury, or subsequent Artery Reassembly and cardiac regeneration. |