The Role of Serum Response Factor in Early Coronary Vasculogenesis

Abstract

Defects in vascular development are a major cause of fetal demise and congenital cardiovascular disease. Knowledge is scarce concerning both embryonic vascular cell progenitors and the underlying regulatory mechanisms that determine their commitment to various vessel cell lineages. During early cardiovascular development, the proepicardium (PE) is the major source of vascular progenitors. The PE is a transient embryonic structure found at stages 16 and 17 in the chick, at 9.5 days postcoitum (dpc) in the mouse, and at approximately 5 weeks in the human that consists of mesothelial and mesenchymal cells overlying the septum transversum (ST). Cells within the PE undergo a complex process of development and differentiation that involves at least two directed waves of migration and epithelial-to-mesenchymal transitions (EMT). The PE cells make contact with the inferior surface of the developing myocardium, migrate over the surface of the heart forming the epicardium, and penetrate into the myocardium and give rise to subepicardial mesenchymal cells (SEMCs). The SEMCs subsequently migrate throughout the developing heart giving rise to the entire coronary vasculature consisting of fibroblasts as well as endothelial and smooth muscle cells [32]. Serum response factor (SRF) is essential for mesoderm formation during embryonic development [2]. A necessary role for SRF in the development of vascular smooth muscle from yet to be characterized PE-derived coronary vascular precursor cells has been demonstrated in avian explant models [15]. The role of SRF in vivo during some of the earliest steps in mammalian PE-mediated vascular development, however, is less well studied, and our recent observations suggest that it likely is more complex. This brief review aims to discuss the role of SRF during early coronary vasculogenesis as it relates to development of the PE.