TRANSCRIPTIONAL MECHANISMS OF ENDOTHELIAL FUNCTION AND DIFFERENTIATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. During embryonic development the early vascular plexus forms through the process called Vasculogenesis, In response to growth factors, endothelial precursor cells differentiate to endothelial cells and migrate to form new blood vessels. The early vascular plexus is then extended through angiogenesis in which new vessels are formed from existing vessels. In adults, angiogenesis is also involved in multiple physiological and pathological (e.g. tumor angiogenesis) conditions. VEGFR family of receptor tyrosine kinases (RTKs) are crucial for vascular development during embryogenesis as well as physiological and pathological angiogenesis in adults.Multiple transcription factors, including ETS and hypoxia inducible factors (HIFs)have been implicated in establishing endothelial cell-specific gene expression. So, we hypothesize that an angiogenic signal-ETS1/HIF-2alpha axis regulates transcription of VEGFRs and other key genes in vascular endothelium. In this study, using gain-in- and loss-of-function approaches with mouse embryonic stem cell (ES cell) differentiation system, we will test whether ETS1 and HIF-2alpha regulate VEGFR expression during endothelial differentiation. Analysis will be performed with ES cells, ES cell-derived endothelial progenitor cells and endothelial cells to test the hypothesis that during endothelial differentiation VEGFR1 and VEGFR2 chromatin domains are regulated by ETS1 and HIF-2alpha. In addition, we will determine the importance of the functional co-operation of ETS1 and HIF-2alpha during vascular development by generating mice lacking both ETS1 and HIF-2alpha. Angiogenesis is critical for certain pathological disorders including tumor growth/metastasis. Information gleaned from these studies will contribute to our understanding of the molecular mechanisms of angiogenesis and hopefully will lead to novel therapeutic modalities.