Epicardial regulation of coronary vasculature development
Fetal coronary vasculature development arises from the integration of endothelial cells (ECs) with supportive mural cells and signals stemming from the epicardium. Synchronized with the development of the coronary vasculature, the epicardium undergoes epithelial-to-mesenchymal transformation (EMT); a process that regulates epicardial cell migration, differentiation and growth factor secretion. Genetic mouse models with limited epicardial EMT show impaired subepicardial mesenchyme formation in addition to dysfunctional vasculature networks, yet the mechanisms underlying the appearance of this catastrophic phenotype are unknown. Our lab aims to identify the specialized epicardial cells and signaling programs responsible for the distinct patterning of vascular pathfinding cues during coronary vasculature development. To achieve this goal, we utilize cell-lineage tracing models coupled with the investigation of transcriptional programs of epicardial cells and ECs by single cell RNA sequencing. The epicardium’s role in facilitating arterio-venous specification and patterning is emerging as a novel mechanism to support regenerative-based medicine. Our essential goal is to identify fetal vascular guidance mechanisms that may be harnessed for the development of therapies to treat vascular diseases.
Restoration of angiogenic cues for the treatment of ischemic heart disease
Coronary artery disease (CAD) is the leading cause of myocardial dysfunction and mortality worldwide. CAD occurs when the constriction and/or blockage of blood vessels restricts oxygen and nutrients to the myocardium leading to a myocardial infarction (MI). As the adult heart is unable to regenerate following MI, our lab aims to identify the cellular and molecular programs required to rebuild coronary arteries and mitigate cardiac inflammation and fibrosis following an ischemic event. Utilizing knowledge from our studies conducted during fetal development in the epicardium, we are investigating vascular mural cell-lineages and paracrine signaling programs in order to promote new vessel formation following MI. Restoration of fetal angiogenic factors in the adult heart is accomplished with in vivo delivery of adeno-associated viral vectors followed by evaluation of de novo coronary vessel formation and cardiac repair in response to acute ischemic injury in the heart.