9 April

Novel mechanism for the formation of large diameter blood vessels

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Researchers from the groups of Catherine Robin (Hubrecht Institute) and David Traver (University of California San Diego) identified a novel mechanism in the formation of large diameter blood vessels. Using state-of-the-art imaging techniques, they found that endothelial cells first form a scaffold in the future lumen of the vessel. Consequently, the cells from the scaffold gradually migrate to the outside of the structure and wrap around it to form the vessel wall. This leaves the lumen cleared from any structures and ready to support blood flow. With these findings, the researchers show for the first time that large diameter vessels can be formed by an orchestrated movement of endothelial cells without the need of cell division. The study was published in Nature Cell Biology on the 9th of April.

Building a large hollow tube such as a large diameter vessel from scratch is a challenging task. The main issue is to counteract external forces coming from the fast-growing tissue surrounding the vessel and to prevent the hollow space, or lumen, from collapsing. A potential solution to this issue is to first form a solid tube and then create a lumen by the programming cell death in the center when these cells are not needed anymore. This mechanism called cord hollowing is used for example during intestinal development. However, this is only possible when the loss of numerous cells can be afforded. However, this certainly not the case during blood vessel development when a limited pool of endothelial cells needs to quickly assemble into a functional vessel.

Two-step process

Researchers from the groups of Catherine Robin (Hubrecht Institute) and David Traver (University of California, San Diego) therefore decided to investigate how large vessels are formed. They used the zebrafish model to study and compare the formation of the dorsal aorta – 2 cells in diameter – and the posterior cardinal vein (PCV) – which is nearly ten times larger. The found that the formation of the PCV does not depend on cell death, as cord hollowing does, nor does it depend on cell division to increase the pool of cells. Rather, it relies on a new two-step process.

Spokes of a wheel

First, endothelial cells form a scaffold in the future lumen of the vessel that consists of pillar like structures that the researchers termed struts. Bart Weijts, researcher on the project explains: “These struts can be seen as the spokes of a wheel, they maintain the shape of the wheel and withstand external forces. Initially there are only spokes and no rim (vessel wall) and gradually each spoke is deconstructed with the cells from that spoke migrating outwards forming the rim. When all spokes have been deconstructed, the rim (vessel wall) is complete and supports blood flow.” By using a sophisticated laser ablation setup, the researchers were able to sever single struts and found that severing nearly all struts resulted in the collapse of the vessel. “Much like a wheel that cannot maintain its shape with the loss of a couple of spokes”, says Weijts. These data provided the definitive proof that struts provide structural support during the formation of the vessel.

 

Illustrative picture
The formation of large diameter blood vessels occurs in two phases. First, the cells form a scaffold in the future lumen of the vessel. Second, this scaffold is gradually deconstructed with the cells from the scaffold migrating to the outside where they start to form the vessel wall. From: Weijts et al., Nature Cell Biology (2021).
The missing link

A single strut consists out of a string of endothelial cells that are connected head-to-toe and can be as thin as one endothelial cell in diameter. While the laser ablation experiments provided clear evidence that struts are required to maintain the shape of the lumen, the researchers were puzzled how struts containing only a few cells could withstand strong external forces. The solution to this problem was found when the researchers started to simultaneously image the endothelial cells and the red blood cells – also called erythrocytes. The first erythrocytes are already present before there is a functional blood vessel and are formed alongside the endothelial cells forming the PCV (the large diameter vessel). Prior to the formation of struts, these erythrocytes are mixed with the endothelial cells. As a results of strut formation, they become trapped into compartments, with some compartments tightly packed with erythrocytes. “Then we realized that these filled compartments provide the actual structural support, rather than the strut itself,” says Weijts. Because struts are gradually deconstructed, these compartments are step-wise lost, providing the required support until the last one is resolved, and releasing the erythrocytes into the now established blood stream.

Illustrative image
The formation of the scaffold (magenta) traps erythrocytes (green) into compartments, some tightly filled. These compartments thereby form rigid structures that provide sufficient support to withstand external forces. From: Weijts et al., Nature Cell Biology (2021).
Rigid structures

Overall, by identifying a new model that is different from the current dogmas in the field, this study for the first time shows how the embryo is able to form large diameter vessels, by using only a limited pool of endothelial cells. By collaborating with the erythrocytes, the endothelial cells form rigid structures that withstand external forces and thereby maintain the shape and lumen of the blood vessel.

Publication

‘Endothelial struts enable the generation of large lumenized blood vessels de novo’. Bart Weijts, Iftach Shaked, Mark Ginsberg, David Kleinfeld, Catherine Robin & David Traver. Nature Cell Biology (2021).

 

 

Catherine Robin is group leader at the Hubrecht Institute and is also appointed at the University Medical Center Utrecht.