Blood Vessel Size Control

Many vascular structures are organized in a hierarchical pattern, resembling trees. This organization plays a crucial role in the efficient distribution of blood throughout the body. We are studying how blood vessels know which size they should have in order to properly built such trees. We identified a zebrafish homologue of endoglin, a gene associated with hereditary hemorrhagic telangiectasia (HHT), a vascular disease in humans. In zebrafish mutants for this gene, blood vessels are abnormally large, resulting in aberrantly patterned vascular trees. We also found that the size of a given blood vessel is dependent on the shape of the cells building this blood vessel, and that cells in endoglin mutants fail to obtain their proper shape. We could also determine that cells change their shapes in response to changes in the magnitude of blood flow they experience. Recent work has elucidated an unexpected cell-autonomous function of endoglin signaling, specifically in vein cells, whereas the loss of endoglin affected individual arterial endothelial cells to a lesser extent. These findings highlight the importance of considering secondary effects, such as changes in blood flow patterns, that may cause differences in vascular patterning observed in mutant animals. Current research aims to understand how endoglin influences cell shapes in distinct cell populations and the mechanisms that allow endothelial cells to properly respond to changes in blood flow.

We also found that cells ensheathing vascular endothelial cells, so called mural cells, play an important role in controlling blood vessel sizes. To study these cells, we generated several transgenic lines in which mural cells were engineered to express fluorescent proteins, enabling detailed imaging of their interactions with endothelial cells. Understanding how mural cells influence endothelial cell shapes and blood vessel sizes is a crucial research question in the laboratory.

Publications

Diwan Z., Kang J., Tsztoo E., Siekmann A.F. (2024). Alk1/Endoglin signaling restricts vein cell size increases in response to hemodynamic cues. Angiogenesis. 10;28(1):5.

Siekmann A.F. (2023). Biology of vascular mural cells. Development. 15;150(16):dev200271.

Leonard E.V., Figueroa R.J., Bussmann J., Lawson N.D., Amigo J.D., Siekmann A.F. (2022). Regenerating vascular mural cells in zebrafish fin blood vessels are not derived from pre-existing mural cells and differentially require Pdgfrb signalling for their development. Development. 149(7):dev199640.

Sugden W.W., Siekmann A.F. (2018). Endothelial cell biology of Endoglin in Hereditary Hemorrhagic Telangiectasia. Current Opinion in Hematology, May;25(3):237-244.

Sugden W.W., Meissner R., Aegerter-Wilmsen T., Tsaryk R., Leonard E.V., Bussmann J., Hamm M.J., Herzog W., Jin Y., Jakobsson L., Denz C., Siekmann A.F. (2017). Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues. Nature Cell Biology. 19(6):653-65