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New insights about the role of WT1 in blood vessel formation during development and repair

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Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia

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[eng] The pleiotropic WT1 transcription factor (WT1) was first discovered in renal tumours. It contains four zinc-finger motifs at the C-terminus which are important for DNA binding to activate gene expression and is also involved in post-transcriptional processes. The expression of WT1 is essential during development of multiple organs, among them the cardiovascular structures. In the developing heart, WT1 is strongly expressed in the epicardium, and in cardiac endothelial cells. After cardiac injury, WT1 is temporally upregulated in both lineages in the infarcted area and border zone, which points to a potential role for WT1 in cardiac repair and regeneration. 
In this thesis, we focused on the role of Wt1 in endothelial cells, particularly in cardiac endothelial cells during coronary vessel formation, and in the adult heart after myocardial infarction. To support some of these findings, the mouse retinal vasculature was used as a model for two-dimensional angiogenic studies. We have demonstrated that Wt1 is present in CECs during coronary development, and that Wt1 deletion abrogates for endothelial proliferation, migration, and maturation during both retinal and coronary vasculature formation in vivo. Also, RNAseq analysis of embryonic Wt1-KOΔEC CECs suggests that Wt1 controls several downstream pathways. However, the importance of Wt1 functions in neovascularization in the adult heart after injury, specifically after 14 days of MI, has proven to be limited. The so-called recapitulation of embryonic programs in the neovascularization processes arising after injury was not sufficient for Wt1 to exert a differential effect on the adult heart after myocardial infarction. We observed no significant functional changes in cardiac output, assessed by ECG imaging, nor in tissue remodelling, visualized by analysis of the fibrotic scar in the infarcted region. However, we did observe changes in Wt1-KOΔEC CECs at the molecular and transcriptomic level, suggesting that WT1 may activate some genetic programmes in these cells, even if its effects are not able to alter evident cardiac functions.

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Tesis Doctorals - Departament - Biologia Cel·lular, Fisiologia i Immunologia

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New insights about the role of WT1 in blood vessel formation during development and repair