The role of the TGFb-Par6 polarity pathway in endothelial-to-mesenchymal transition and angiogenesis

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Angiogenesis, the formation of new blood vessels from pre-existing ones, is required for the development of the circulatory system, for organ development in general, and for the normal function of organs in an adult individual. Angiogenesis has also been demonstrated to be an essential mediator of disease, including cancer. Transforming growth factor-beta (TGFb) promotes angiogenesis under specific conditions, but how this effect is achieved is not well understood. Here I propose that TGFb promotes angiogenesis by inducing endothelial-to-mesenchymal transition (EnMT), a process of cellular plasticity that allows cells initially immersed in a static cell layer, to acquire the capacity to migrate. More specifically, I propose that TGFb induces EnMT and angiogenesis by activating the TGFb-Par6 signaling pathway, which targets the endothelial cell-cell contacts to permit angiogenesis. To prove these hypothesis I will use three-dimensional cultures of endothelial cells under physiologically relevant conditions, which reproduce the essential steps of the angiogenesis process in an actual organism. I will apply biochemical, genetic and imaging approaches using these in vitro models to first, demonstrate that EnMT is required for angiogenesis and second, that TGFb, specifically through the activation of the Par6 pathway, induces EnMT and promotes angiogenesis. This research program will significantly improve our knowledge and understanding of the angiogenesis process, with obvious impact on basic and applied life sciences, including health sciences. This program will also contribute to the academic formation of students in biological sciences and to the training of highly qualified, internationally competitive Canadian scientists and professionals.