Signaling pathways that regulate vascular lumen formation

The acquisition of lumen in a developing vessel is a critical step in the morphogenesis of the vascular system and it is essential to the circulation of blood. Studies in zebra fish have indicated that fusion of multiple vesicles participate in the patency of intersomitic vessels. This concept of vacuole/vesicle fusion has been also supported by a large body of experimental data from in vitro studies. However, the molecular mechanisms and signaling underpins that regulate lumen morphogenesis have remained for the most part unknown. Performing a series of loss‐of‐function studies specifically in endothelial cells, we found that beta 1 integrin and Notch are two signaling pathways that regulate lumen formation. Absence of beta 1 integrin in endothelial cells results in lack of endothelial polarity, accumulation of par6 and absence of lumenized vessels in the majority of small/medial arteries. These findings indicate that beta1 integrin is an essential initial step in the program of lumen formation. While mice that lack endothelial Notch showed a lumen, its maintenance requires the activity of this signaling pathway. Constitutive loss of Notch in endothelial cells results in vascular stenosis in larger vessels. Interestingly, loss of Notch at later stages of development lead to occluded vessels that result from the grow of endothelial cells into the lumen of previously developed vascular structures. Together these findings constitute the first examples of signaling pathways that are critical to different stages of vascular lumen development.