Analysis of the shear stress-induced transcriptional program during vascular development
Bioinformatics and Theoretical Biology
Biophysics
Cell Biology
Final Report Abstract
Properly patterned blood vessels are of importance to ensure the distribution of the right amounts of blood to all organs and tissues. Consequently, an aberrantly formed vasculature can lead to hypoxic conditions and disease. Arterio-venous malformations (AVMs) are often observed in the human genetic disease hereditary hemorrhagic telangiectasia, caused by mutations in the transforming growth factor beta pathway components Alk1 and Endoglin. We have generated zebrafish mutants in Endoglin to better understand the underlying mechanisms causing AVMs. Our results show that blood vessels in wildtype animals need to constrict during embryonic development in order to prevent AVMs from forming. This constriction is defective in endoglin mutants. Further, cell shape changes underly these constrictions and it is defects in these shape changes that precipitate AVMs in endoglin mutants rather than changes in endothelial cell numbers. Through cell transplantation experiments we showed that endoglin is required endothelial cell autonomously and that blood vessels containing mutant cells fail to constrict. This leads to aberrant blood flow patterns with some vessels (the shunts) carrying too much flow, while others carry too little flow. Our results further suggest that these changes in flow influence the expression of flow responsive genes in endoglin mutants rather than endoglin serving as a flow sensor. Shear stress alone applied in 2D cell culture does not recapitulate the changes observed in embryos, suggesting that cellular responses to forces other than shear are controlled by endoglin. Together, our results reveal how endoglin signalling intricately controls blood vessel diameters through effects on the dimensions of endothelial cells.
Publications
- 2017. Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues. Nature cell biology 19, 653-665
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.
(See online at https://doi.org/10.1038/ncb3528) - 2018. Endothelial cell biology of Endoglin in hereditary hemorrhagic telangiectasia. Curr Opin Hematol. 25(3), 237-244
Sugden, W.W., Siekmann, A.F.
(See online at https://doi.org/10.1097/moh.0000000000000419)
