Specification of arterial, venous, and lymphatic endothelial cells during embryonic development

Abstract

The groundbreaking discovery about arterial and venous expression of ephrinB2 and EphB4, respectively, in early embryonic development has led to a new paradigm for vascular research, providing compelling evidence that arterial and venous endothelial cells are established by genetic mechanisms before circulation begins. For arterial specification, vascular endothelial growth factor (VEGF) induces expression of Notch signaling genes, including Notch1 and its ligand, Delta-like 4 (Dll4), and Foxc1 and Foxc2 transcription factors directly regulate Dll4 expression. Upon activation of Notch signaling, the Notch downstream genes, Hey1/2 in mice or gridlock in zebrafish, further promote arterial differentiation. On the other hand, the orphan nuclear receptor COUP-TFII is a determinant factor for venous specification by inhibiting expression of arterial specific genes, including Nrp1 and Notch. After arterial and venous endothelial cells differentiate, a subpopulation of venous endothelial cells is thought to become competent to acquire lymphatic endothelial cell fate by progressively expressing the transcription factors Sox18 and Prox1 to differentiate into lymphatic endothelial cells. Therefore, it has now evident that arterial-venous cell fate determination and subsequent lymphatic development are regulated by the multi-step regulatory system associated with the key signaling pathways and transcription factors. Furthermore, new signaling molecules as additional regulators in these processes have recently been identified. As the mechanistic basis for a link between signaling pathways and transcriptional networks in arterial, venous and lymphatic endothelial cells begins to be uncovered, it is now time to summarize the literature on this exciting topic and provide perspectives for future research in the field.

Fig. 1

A model for molecular pathway for arterial, venous and lymphatic cell fate determination in vertebrate embryo. The VEGF-VEGFR2/Nrp1 pathway activates Notch signaling in angioblasts, leading to the specification of arterial cell fate, while crlr controls VEGF expression. Dep1 acts upstream of the VEGF-activated PI3K pathway. Foxc1 and Foxc2 directly regulate Dll4 and Hey2 expression, presumably downstream of VEGF signaling. Sox7/18 and snrk-1 may act upstream of grl (the Hey2 homolog in zebrafish). EphrinB2 is a downstream target of Notch. In venous endothelial progenitors, COUP-TFII suppresses Nrp1 and Notch activation and promotes venous cell fate. A subpopulation of venous endothelial cells subsequently expresses Sox18 and Prox1, thereby inducing lymphatic cell fate. COUP-TFII also contributes to lymphatic gene expression by interacting with Prox1.