How do blood vessels of different sizes develop?
Project title: Analysis of the cytoskeleton in controlling endoglin-dependent endothelial cell shape changes in response to mechanical forces
Principal investigators: Arndt F. Siekmann, Britta Trappmann
Project time: 11/2017 - 12/2018
Project code: FF-2017-21
The vascular system in the human body consists of large and small arteries and veins which are connected via even smaller capillary blood vessels. Researchers at the Cells-in-Motion Cluster of Excellence at the University of Münster are trying to understand why and how different diameters evolve during embryonic development. What is already known today is that blood-flow mediated shear stress widens the vessels, because endothelial cells which line these vessels expand under the pressure of the blood-flow. However, there is another reaction to the shear stress – specifically, during the development of the vascular system. Münster researchers have just recently discovered that the diameter of blood vessels can also decrease depending on blood-flow. It is precisely this decrease which is decisive for the extent to which the vascular system is branched. A group of researchers led by Dr. Arndt Siekmann were able to observe how new blood vessels shrank in zebra fish. To begin with, their endothelial cells are round in shape – but when blood flows through a vessel, the cells are elongated as a result of the shear stress. At the same time, they retain their area. This means that the endothelial cells are no longer round but elongated. When all the endothelial cells react in this way, the vessel contracts and its diameter shrinks.
It is evidently the endoglin gene which is decisive for this mechanism. This has been proved – at least for zebrafish – by the group of researchers led by Arndt Siekmann. If the endoglin gene does not function perfectly, the result is a disease of the blood vessels called Morbus Osler. Patients who have this disease have so-called arteriovenous malformations, with arteries being connected directly to veins. The small capillaries which normally supply the tissue with nutrients are missing. As a result, in Morbus Osler patients some parts of the tissue are undersupplied. In the absence of endoglin, the endothelial cells’ area evidently remains round in shape, and the cells no longer contract. The result is a redistribution of the blood-flow from the capillaries to some of the arteries and veins, which now remain too large. The researchers also discovered that the capillaries with a poor blood supply shrink during their development.
The aim which the researchers at the Cells-in-Motion Cluster of Excellence now have is to reveal the mechanisms behind these malformations. For their initial investigations they plan to use a model to replicate blood vessels, simulate the blood-flow and determine which molecules are decisive for the shrinking mechanism.
To this end, biologist Dr. Arndt Siekmann is collaborating with Dr. Britta Trappmann, a biomedical engineer, who with her group is developing a three-dimensional, synthetic tissue model with tiny tubes made from a special hydrogel. The researchers plan to line the pre-formed tubes with endothelial cells and then pump fluid through the new blood vessel. In this way they can observe how the endothelial cells react to the shear stress. Their hypothesis is that the tubes will also contract in the tissue model. Then the researchers could look to see which molecules are responsible for the change in tube sizes.
In the second stage, Arndt Siekmann plans to apply the findings to zebrafish to see whether they also hold true in living organisms – and whether there is a possibility of halting malformations during the development process. The experiments could indicate an approach to find a possible treatment for Morbus Osler patients. Many more research projects will be required, however, before that stage is reached.