Formation of the vasculature is a critical step within the developing embryo and its disruption causes early embryonic lethality. This complex process is driven by a cascade of signaling events that controls differentiation of mesodermal progenitors into primordial endothelial cells and their further specification into distinct subtypes (arterial, venous, hemogenic) that are needed to generate a blood circulatory network. Hemogenic endothelial cells give rise to hematopoietic stem and progenitor cells that generate all blood cells in the body during embryogenesis and postnatally. We focus our discussion on the regulation of endothelial cell differentiation, and subsequent hemogenic specification, and highlight many of the signaling pathways involved in these processes, which are conserved across vertebrates. Gaining a better understanding of the regulation of these processes will yield insights needed to optimize the treatment of vascular and hematopoietic disease and generate human stem cell-derived vascular and hematopoietic cells for tissue engineering and regenerative medicine.
