Elucidating the transcriptional mechanisms regulating shear stress mediated gene expression and their role during blood vessel pruning

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The vasculature consists of a ramified network of endothelial tubules. In order to establish this vascular network, endothelial cells must coordinate a variety of different cellular processes. Endothelial cells need to migrate in response to chemotactic cues, proliferate and subsequently differentiate. Recent genetic studies have uncovered a number of key players that are involved in blood vessel sprouting. These include VEGF, Notch and G-protein coupled receptors. However, little is known about the spatial and temporal activation of these pathways within a given endothelial cell and how the inputs from these divergent pathways are integrated. In particular, we do not understand how neighbouring blood vessels navigate in close proximity to one another without responding to the same guidance cues. The proposed research aims to address three fundamental questions in angiogenesis, making use of recent progress in in vivo imaging and genetic manipulations in the zebrafish model system. We will delineate the contribution of endothelial cell divisions during vascular patterning and study the involvement of asymmetrically distributed cell fate determinants in this process. We will then address the question how regional differences are established during angiogenic sprouting and how chemokine signalling contributes to this process. Finally, we will carry out a screen aiming at the identification of new players important for proper blood vessel sprouting to occur.