ZEB1 signalling in endothelial cell heterogeneityTools Horder, Joseph (2025) ZEB1 signalling in endothelial cell heterogeneity. PhD thesis, University of Nottingham.
AbstractEndothelial cells (ECs) are at the core of vascular homeostasis, enabling angiogenesis, immune cell trafficking and barrier function. Zinc-finger E-box binding protein 1 (ZEB1) has recently emerged as a central regulator of EC plasticity, particularly through its roles in endothelial-to-mesenchymal transition (EndoMT) and vessel remodelling. Here, we test the hypothesis that ZEB1 expression dynamically modulates EC heterogeneity and specialisation during both developmental and pathological angiogenesis. Using siRNA knockdown (KD) and chromatin immunoprecipitation (ChIP)-seq in human umbilical vein endothelial cells (HUVECs), we show that ZEB1 broadly influences genes controlling cell adhesion, immune responses and tip-cell identity and cooperates with ETS and AP-1 transcription factors. Analyses of publicly available scRNA-seq datasets revealed ZEB1 enrichment in specialised EC subpopulations across multiple tissues, including venous-capillary ECs in the spleen, tip cells in the retina, tumour-associated ECs and floor ECs of the subcapsular sinus of the lymph node. Further analysis of myocardial infarction scRNA-seq data demonstrated that ZEB1 contributes to a partial EndoMT phenotype, wherein ECs retain some endothelial traits while acquiring mesenchymal characteristics. A text-mining approach further uncovered a proposed ZEB1 regulatory network in EndoMT. Finally, we demonstrate that adult induced ZEB1 knockout in adult retina ECs does not alter vascular area or number of ECs. Collectively, these findings position ZEB1 as a context-dependent modulator of ECs.
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