Analysis of Notch signalling pathway activation in controlling arteryformation during sprouting angiogenesis

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The vasculature is one of the first organs formed during embryonic development important for providing the body with nutrients. After the first blood vessels have formed from precursor cells, new blood vessels sprout from these, which connect to a network. This process is called angiogenesis. During angiogenesis, endothelial cells must grow in a controlled manner into non-perfused tissues, where they form tubes. These must eventually connect in a coordinated fashion with the already existing blood vessel system in order to ensure proper blood flow from arteries into veins. The growth takes place via the specification of so-called "tip" cells, which lead newly growing blood vessel sprouts and "stalk" cells, which follow the tip cells. We and other laboratories have been able to identify several signalling pathways important for tip and stalk cell specification. One of these pathways is Notch. These studies provided a concept in which a notch ligand, dll4, is expressed in tip cells during angiogenic sprouting, which activates Notch signalling in stalk cells, thereby preventing them from becoming tip cells themselves. Observations in the last few years in my laboratory, however, made us doubt this concept. For instance, we could observe that new blood vessel sprouts mainly originated from veins, and that the tip cells of these venous sprouts subsequently formed new arteries. It was also known that arteries need activation of the Notch signalling pathway for their differentiation. How could tip cells, then, which showed a low activation of the Notch signalling pathway become arteries? New time-lapse recordings in which we were using a reporter to monitor the activation of the Notch signalling pathway in zebrafish have now shown activation of the Notch signalling pathway in tip and not in stalk cells. In this application we will now examine how tip and stalk cells coordinate Notch signalling pathway activation. We will investigate how Transforming Growth Factor beta (TGF beta) signalling affects Notch pathway activation. In addition, we will explore how these two pathways influence the expression of a chemokine receptor, cxcr4a, which is important for the proper migration of tip cells. Finally, we will study angiogenesis in a tissue in which only veins and no arteries are being formed. In this setting, we would expect the Notch signalling pathway to not significantly influence vein formation. In summary, we expect new insights into the coordinated regulation of angiogenesis and artery formation and the influence of both the Notch and TGF beta signalling pathways on these processes.