The proposed study aims to elucidate the role of the Slug transcription factor in regulating sprouting angiogenesis, and the underlying mechanism employed. Slug (Snai2) is a member of the highly-conserved Snail family of transcription factors and is known to induce epithelial-to-mesenchymal transition (EMT), an important process for both embryonic development and pathological conditions such as tissue fibrosis and cancer metastasis. A similar process occurs in endothelial cells (EC), named endothelial-to-mesenchymal transition (EndoMT), and this can also be regulated by Slug. Our recent study demonstrated that Slug expression in EC is vital for sprouting angiogenesis in vitro, potentially by inducing a partial EndoMT. Interestingly, vascular defects have not previously been documented in Slug-deficient mice. However, in a preliminary study using these mice we have observed defects in both developmental and pathological angiogenesis. We have also reported that over-expression of Slug promotes enhanced EndoMT-like behaviors in angiogenic ECs. However, the exact targets and mechanisms involved in Slug-mediated EndoMT during sprouting angiogenesis are unclear. The work proposed will firstly test whether the vascular defects seen in Slug-deficient mice are due to loss of Slug in the EC themselves (all evidence to date points to this being the case), and will then examine how the level of Slug expression in EC determines whether cells undergo a partial EndoMT to form new vessels, or a complete EndoMT which resembles immature and disorganized tumor vasculature. Finally, we will test whether EndoMT-initiating factors such as HGF and TNF? promote angiogenesis by inducing Slug gene expression and protein stability. Given the existing studies and our preliminary data, we hypothesize that the level of Slug expression induced by pro-EndoMT factors controls sprouting angiogenesis in vivo. Completion of these aims will significantly enhance our understanding of the basic mechanisms underlying new blood vessel formation, shed light on unique and novel characteristics of tumor angiogenesis, and present new drug targets for pro- or anti- angiogenic therapies. The scope and potential public health impact of the proposed study fits well with the missions of NHLBI and NCI to promote healthy living by preventing vascular diseases and combating cancer.
Too many, too few, or poorly-functioning blood vessels can lead to numerous pathologies, thus a deep understanding of how blood vessel growth is regulated has obvious clinical implications. As Slug is a key transcription factor in the process o angiogenesis, controlling its expression and action could have profound affects on blood vessel growth. Thus we hope to identify upstream activators of Slug, its mode of action, and its immediate targets, several of which we have already identified. These may provide multiple new targets for the development of drugs that restore normal vessel growth.
