Endothelial cell specification - crossroads in vascular development

The cardiovascular system is one of the earliest organ systems to develop in all vertebrates. Disturbances in the development of the vasculature will consequently result in severe malformations. To understand the pathology of cardiovascular diseases it is crucial to understand the composition and development of the cardiovascular system in detail. To form a functional vasculature, endothelial cells differentiate into arterial, venous and lymphatic cells. The arterial cells form the arteries that transport blood from the heart towards all perfused tissue; the venous cells assemble to form the veins that return the blood from the peripheral tissues back to the heart. Lymphatic vessels have a somewhat different function in that they collect interstitial fluid and control fluid homeostasis. We shed light on several aspects of endothelial specification, thereby clarifying certain issues and opening up new paths in the understanding of endothelial differentiation during vascular development. Our data revealed an important role for the SoxF transcription factor, Sox7, in vascular development. sox7 loss of function in zebrafish results in defective blood circulation. We reveal a disturbance in the arterial-venous fate of specific endothelial cells, resulting in ectopic connections between specific arteries and veins. We also place sox7 in the arterial signaling pathway, by loss-of-function and genetic interaction studies of several artery-specific genes. Furthermore we shed new light on the function of sox18 in vascular development, and reveal only a partially redundant and spatially specific function of sox18 in arterial-venous specification. After the arterial-venous vasculature is established within the murine embryo, a subset of venous cells will differentiate into lymphatic endothelial cells. These lymphatic endothelial cells will form the lymphatic vasculature. We report that in zebrafish prox1 as well as sox18 and coupTF are dispensable for lymphatic specification. Furthermore, we analyze the details of prox1a expression, which becomes restricted to lymphatic cells only at later stages during lymphangiogenesis. These results are in contrast to lymphatic regulation in mice, thereby suggesting that the lymphatic specification is differentially regulated between fish and mice. Previous data together with our new data hint for these genes to be potential entry points for targeted therapies in cardiovascular diseases, tumor growth and metastasis. It also underscores the importance of detailed developmental research, to increase our knowledge of the regulation of the vasculature in normal and pathological development.