Mechanisms that Govern Vasculogenesis

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PROJECT SUMMARY/ABSTRACT Ischemic heart disease (IHD) is the leading cause of death in the world and current therapies are limited due to the inability to promote remuscularization of the injured heart. In the absence of remuscularization, the injured heart forms a scar following a myocardial infarction (MI) that can progress towards heart failure. Insufficient vasculature and impaired perfusion are critical factors affecting the morbidity and mortality observed in IHD. These cardiovascular diseases are chronic, debilitating, lethal and they warrant the development of novel therapies. One approach is to promote vasculogenesis in order to enhance heart regeneration. Clinical trials using exogenous factors to treat IHD have shown conflicting results that have been attributed to the inability of such factors to drive vasculogenesis. Therefore, new therapies that can fully drive vasculogenesis for the treatment of IHD are warranted. Our laboratory has shown that the ets variant factor 2 (ETV2) is a transcription factor that is both necessary and sufficient for the development of hematoendothelial (HE) lineages as loss of ETV2 is embryonically lethal due to the absence of all blood and vasculature. Recent evidence from our laboratory suggests that ETV2 functions as a pioneer transcription factor for the HE lineage. Pioneer transcription factors bind and relax condensed chromatin in order to drive gene expression changes necessary for the development or specification of cell lineages. Our preliminary data shows that ETV2 physically interacts with BRG1, a chromatin remodeling enzyme, which has been shown to collaborate with other pioneer transcription factors in the development of different lineages. However, it remains unclear how ETV2-BRG1 interactions might be related to HE development and the pioneer function of ETV2. Furthermore, overexpression of ETV2 has been shown to reprogram fibroblasts into functional endothelial cells in vitro. However, it is not known whether ETV2 overexpression can be used in vivo in a large animal model to reprogram fibroblasts after a MI to enhance vasculogenesis in order to treat IHD. Therefore, the overall goal of this proposal is to develop therapeutic strategies for IHD by understanding the mechanisms that govern vasculogenesis. I hypothesize that ETV2 drives HE lineage development in a BRG1 dependent fashion and that in vivo overexpression of ETV2 will enhance cardiac regeneration by promoting vasculogenesis. I will test this hypothesis by pursuing the following aims: (1) to define the role of BRG1 in the pioneer function of ETV2 in the HE lineage, and (2) to define the capacity of in vivo reprogramming by ETV2 following cardiac injury using a swine model. Completion of these studies will enhance our understanding of how ETV2, as a pioneer factor, targets and relaxes condensed chromatin in a BRG1-dependent fashion to drive HE development and vasculogenesis. These studies will also identify new mechanisms that can enhance reprogramming strategies and potentially lead to the development of new therapies for cardiovascular disease.