Mariggi, G.; (2012) Connecting the tips – a study on sprout fusion in angiogenesis. Doctoral thesis , UCL (University College London).

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Abstract

Angiogenesis is characterized by the sprouting of new vessels from pre-existing ones, with sprouts headed by a specialized endothelial cell (EC) known as the tip cell. The trailing ECs are referred to as stalk cells and help form the vessel proper and lumenize. Newly formed sprouts must come into contact with adjacent tip cells via filopodia to fuse and lumenize to form an additional functional vessel loop able to support blood flow. Here I describe the process of anastomosis in detailed spatial and temporal resolution. Interestingly tip cells do no necessarily form a new connection at their first contact but tend to have a “negotiation” phase whilst tip cells are in contact. This time delay is between 1 hour and 2.5 hours suggesting a possible genetic regulation of anastomosis. Interestingly cessation of filopodia activity is observed upon lumenization of the sprouts and not on the establishment of cell junctions. A gene important in fusion cells in Drosophila tracheal morphogenesis (the equivalent of EC tip cells) was investigated for its role in angiogenesis and anastomosis. Knockdown of heca, the homologue of the drosophila headcase gene, leads to precocious and ectopic connections between the Dorsal Lateral Anastomotic Vessels (DLAVs) over the neural tube in zebrafish embryos. Heca’s function does not appear dependent on the TGF/BMP pathway as in the trachea. Gain of function experiments at the whole organism and cell-autonomous level show that Heca overexpression leads to complete lumenization of some of the migrating intersegmental vessels by 26hpf. This suggests that heca’s possible involvement in instructing ECs to form a lumen or to sense the level of oxygenation/requirement to decrease activity may explain the opposing phenotypes observed. Taken together with observations about lumen formation with initiation of flow and the termination of filopodia activity, the data here presented could mean that lumenization is involved dampening EC activation.

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