How do blood vessels form to reliably supply the body with oxygen and nutrients? A research team at the University of Basel has uncovered a key mechanism by which cells join to build new blood vessels. Their study reveals how pushing and pulling forces enable individual vessel segments to connect and form a continuous blood vessel. The findings deepen our understanding of vascular development and provide a foundation for the development of vascularized organoids.
To supply the body with blood, billions of cells must be organized into a highly branched vascular network. This process of blood vessel formation relies on the creation of hollow tubes, which contain a continuous lumen, through which blood can later flow. How endothelial cells change their shape and precisely coordinate their movements during this process has so far been only partially understood.
Using high-resolution live imaging in zebrafish, the researchers led by Professor Markus Affolter and Dr. Heinz-Georg Belting at the Biozentrum have now unraveled this process in unprecedented detail. Their findings, published in the journal eLife , demonstrate for the first time the complete sequence of events by which neighboring lumina connect and merge into a continuous blood vessel.
Cell junctions drive blood vessel formation
During vascular development, endothelial cells remain connected to one another by cell-cell junctions. These junctions must be stable enough to maintain the integrity of the vessel wall while remaining sufficiently dynamic to allow cells to rearrange.
Previous work by the team had shown that specialized membrane protrusions, known as junction-based lamellipodia (JBL), form the leading edge of endothelial cells and are responsible for their rearrangements. The new study now demonstrates for the first time which mechanical forces enable the cells to extend and connect with one another during this process.
Push, anchor and pull
The process starts when a JBL protrusion forms at the tip of an endothelial cell, generating a pushing force that extends the cell forward. At its very tip, the protrusion acts like a molecular anchor that attaches to the neighboring cell, linking the two cells together and stabilizing the developing blood vessel.
Next, pulling forces come into play, drawing the rear of the cell forward and gradually elongating it. "Through this repeated cycle of pushing and pulling, the cells move forward much like an inchworm, progressively extending the lumen," explains first author Dr. Ludovico Maggi. In this way, initially separate segments merge to form blood vessels with uninterrupted lumens.
"We found that the molecule VE-cadherin performs two distinct functions," says last author Heinz-Georg Belting. "It not only acts as the 'glue' that holds endothelial cells together and maintains the stability of the vessel wall but also plays an active role in cell movement. We were also surprised by how remarkably plastic these cells are. Both, stable and highly flexible at the same time."
Implications beyond blood vessels
The study provides the first detailed description of how endothelial cells coordinate their cell-cell junctions and demonstrates that both pushing and pulling forces are essential for the formation of continuous blood vessels. Because virtually all organs develop in close interaction with the vascular system, a better understanding of blood vessel formation also advances our knowledge of organ development.
"Blood vessels are far more than simple supply lines," says Belting. "They accompany the development of almost every organ. Understanding how blood vessels form means understanding a fundamental aspect of organ formation."
In the long term, these findings could help researchers engineer organoids and other laboratory-grown tissues with functional blood vessels, which are crucial prerequisites for faithfully replicating natural organ development in research and regenerative medicine.
eLife
Junctional and Actomyosin Dynamics Drive Endothelial Cell Rearrangements during Vascular Tube Formation.