Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Histol Histopathol. 2010 May;25(5):637-46. doi: 10.14670/HH-25.637.
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.
关于 EphrinB2 和 EphB4 在胚胎早期发育中的动脉和静脉表达的突破性发现，为血管研究提供了一个新的范例，有力地证明了动脉和静脉内皮细胞是在循环开始之前通过遗传机制建立的。对于动脉的特化，血管内皮生长因子（VEGF）诱导 Notch 信号基因的表达，包括 Notch1 和其配体 Delta-like 4（Dll4），以及 Foxc1 和 Foxc2 转录因子直接调节 Dll4 的表达。在 Notch 信号激活后，Notch 下游基因，如小鼠中的 Hey1/2 或斑马鱼中的 gridlock，进一步促进动脉分化。另一方面，孤儿核受体 COUP-TFII 通过抑制包括 Nrp1 和 Notch 在内的动脉特异性基因的表达，是静脉特化的决定因素。在动脉和静脉内皮细胞分化后，一部分静脉内皮细胞被认为通过逐步表达转录因子 Sox18 和 Prox1 获得淋巴管内皮细胞命运而成为有能力分化为淋巴管内皮细胞的细胞。因此，现在很明显，动脉-静脉细胞命运的决定和随后的淋巴管发育是由与关键信号通路和转录因子相关的多步调控系统调节的。此外，最近还发现了新的信号分子作为这些过程中的额外调节因子。随着信号通路和转录网络之间的机制基础在动脉、静脉和淋巴管内皮细胞中开始被揭示，现在是时候总结关于这个令人兴奋的主题的文献，并为该领域的未来研究提供观点了。
