Vascular anomalies and remodeling occur in many congenital and acquired diseases such as cardiovascular malformations, diabetes, hypertension, pulmonary diseases of arteries and veins, peripheral vascular disease and myocardial ischemia and infarction. Defects in vascular development have been identified as a major cause of fetal demise. However, there is a paucity of knowledge of the mechanisms that underlie normal vascular development and particularly regarding the progenitors of endothelial and vascular smooth muscle cells and factors that determine their commitment to blood vessel phenotypes. Additionally, the genetic mechanisms by which these precursors subsequently develop further diversity are not well understood. These mechanisms are likely important for the maintenance of healthy vascular systems and for repair of damage in mature organisms. In mammals coronary vascular development is dependent on transient early embryonic structures within the proepicardium. Cells within the proepicardium migrate over the surface of the heart forming the epicardium and subsequently subepicardial mesenchymal cells (SEMC). SEMC are important for multiple aspects of heart development and give rise to the entire coronary vasculature consisting of fibroblasts, endothelial, and smooth muscle cells. Recent studies in our labs have determined that two transcription factors, Serum Response Factor (SRF) and GATA4, play seminal roles in controlling development of the proepicardium. The focus of this application is to determine the role of one of these factors, SRF, in regulating programs of gene expression required for commitment of proepicardial coronary vascular progenitor cells to vascular development. We will take advantage of transgenic SRF conditional gene knockout animals, recently developed by us, to address the hypothesis that initially SRF is required for formation of the proepicardium. The results of these studies will not only elucidate the underlying transcriptional regulatory mechanisms controlling early coronary vascular development, but should also identify coronary vascular precursor stem cells that may have the potential to lead to therapeutic applications in cardiac regeneration. ? ? ?
