Abstract 245: Cxcl12 Chemokine Signaling Regulates Synchronous Development of Coronary Vessels and Myocardium

Abstract

Introduction: The coronary vasculature plays critical roles in heart functions. Coronary heart disease is a major cause of myocardial infarction and heart failure, which continues to be the leading cause of mortality. However, the mechanisms underlying coronary vessel development and myocardial vascularization are not fully understood. Furthermore, it is not known if myocardial developmental defects caused by lack of vascularization will lead to decreased regenerative capacity of the adult heart. Hypothesis: Synchronous development with coronary vessels is essential for normal morphogenesis and regenerative capacity of the myocardium of zebrafish heart. Methods and Results: Using transgenic reporter fish lines, we observed that during zebrafish heart development, coronary vessels form a close association with a specific subpopulation of cortical cardiomyocytes marked by the transcription factor Gata4. When gata4+ cardiomyocytes emerge onto the surface of the juvenile zebrafish hearts, they follow the tracks of coronary endothelial cells. We previously showed that cxcr4a mutant zebrafish fail to form a vascular network, whereas ectopic expression of Cxcl12b ligand induces coronary vessel formation. In cxcr4a mutant hearts, gata4+ cardiomyocytes fail to associate with coronary vessels. Importantly, cxcr4a mutant zebrafish fail to undergo heart regeneration following injury. Gene expression analysis using RNAseq was performed to dissect the molecular mechanisms underlying synchronous development of coronary vessels and gata4+ cardiomyocytes. Conclusion: Our results suggest that Cxcl12/Cxcr4 chemokine signaling has an essential role in directing cardiomyocyte migration guided by endothelial cells. Poorly developed vasculature in cxcr4a mutants likely underlies defects in myocardial development and decreased regenerative potential of zebrafish hearts.