Cardiovascular diseases have long been the leading cause of mortality and morbidity in the United States as well as worldwide. Despite numerous efforts over the past few decades, the number of the patients with cardiovascular disease still remains high, thereby necessitating the development of novel therapeutic strategies equipped with a better understanding of the biology of the cardiovascular system. Recently, the ETS transcription factor, ETV2 (also known as ER71), has been recognized as a master regulator of the development of the cardiovascular system and plays an important role in pathophysiological angiogenesis and the endothelial cell reprogramming. Here, we discuss the detailed mechanisms underlying ETV2/ER71-regulated cardiovascular lineage development. In addition, recent reports on the novel functions of ETV2/ER71 in neovascularization and direct cell reprogramming are discussed with a focus on its therapeutic potential for cardiovascular diseases.

Previous studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs.