Role of NFAT in the vascular endothelium

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The calcineurin-NFAT signaling pathway is involved in many important processes in our bodies. In particular, we know a lot about the crucial role this pathway plays in the immune system, where it switches on and off many key genes. However, less is known about what it does in other parts of the body. I am interested in understanding the control of blood vessel formation. This work focuses on endothelial cells, which form the inner lining of all vessels and are the first part of blood vessels to form. When NFAT signaling is inhibited, blood vessels do not form correctly. We recently examined mouse embryos that had lost NFAT signaling in the endothelium, and found that they have healthy arteries but defective veins. Arteries transport oxygen-rich blood to capillaries, while veins return the blood to the heart. Although vein endothelial cells are already known to be very different from their arterial counterparts, we do not understand how vein formation and growth is regulated. Based on the observations that veins were not formed correctly in NFAT mutant embryos, we looked at the binding pattern of the NFAT protein NFATc1. This revealed that NFATc1 binds directly to the enhancers (on-off switches) of many genes that are required for vein formation, suggesting that NFAT signaling may directly switch these on. In the project, we will analyse mouse and zebrafish embryos with defective NFAT signaling to establish why veins do not form properly. We will also investigate the enhancers that bind NFATc1 to both understand which genes are directly bound and activated by NFAT, and to find the other proteins which help NFAT function. Lastly, we will also find out how NFATc1 is itself able to switch on specifically in vein endothelial cells.