Characterization of HoxBS, a key regulator in blood vessel formation

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Blood vessel formation is essential in health and disease. The regulatory mechanisms thatcontrol the formation and angiogenic response of endothelial cells are far from understood.We have identified the transcription factor HoxB5 as an important regulator of endothelialcell development by its regulatory role on the flk-1 enhancer. Our preliminary data presentedhere indicate that HoxB5 plays also a key role in blood vessel maturation. In this project wewill: 1) investigate the role of HoxB5 on blood vessel formation in detail using sophisticatedgain and loss of function models in vitro and in vivo. 2) elucidate the molecular mechanism ofthe regulation of Angiopoietin-2 by HoxB5 - an effect that we have discovered in thepreliminary experiments leading to this proposal. Angiopoietin-2 has been implicated inendothelial cell destabilization, which is a prerequisite of angiogenic sprouting. Thus, HoxBSmay control two key steps in angiogenesis -endothelial cell destabilization and activation. 3)position HoxBS within known vasculogenic and angiogenic signaling cascades using in vitroand in vitro models. We will particularly focus on the regulation of HoxBS by microRNAs asin silico prediction indicates that a microRNA that is involved in blood vessel formation has apotential binding site in the HoxBS gene. The data obtained so far suggest a hierarchicallyhigh position of HoxBS within angiogenetic signaling consistent wilh a key role for HoxBS inblood vessel formation.