Molecular Regulation of Vascular Development

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DESCRIPTION (provided by applicant): Our goal is to understand the molecular mechanisms that govern vasculogenesis and angiogenesis. Of primary importance in these processes are the endothelial cells that line the lumen of all blood vessels, playing a key role in the formation, remodeling, and normal physiological function of the vascular system. In addition, endothelial cells are involved in dysfunctional or pathological processes of vessel formation, such as atherosclerosis, wound healing, rheumatoid arthritis and psoriasis. In a genetic screen for early circulatory system genes in mouse embryonic stem (ES) cells and embryos, we identified the novel zinc finger gene, Vascular endothelial zinc finger 1 (Vezfl). VEZF1 is a 56 KD zinc finger transcription factor that binds in a sequence-specific manner to CT/GC-rich regions in the IL-3 promoter as well as in several promoters from endothelial-specific genes. Its expression during embryogenesis is restricted to vascular endothelial cells and their mesodermal precursors in the yolk sac blood islands. In adults, Vezfl is expressed at reduced levels in the endothelium of the capillaries and mature vessels. It is also expressed in bone marrow megakaryocytes. Vezfl is induced during arterial injury and tumor angiogenesis. In light of its restricted pattern of expression we hypothesize that Vezfl regulates molecular processes during the determination and/or differentiation of the vascular endothelial lineage. In support of our hypothesis, molecular genetic approaches including loss- and gain-of-function mutations of Vezfl in mouse embryos indicate that Vezfl acts in a dosage-dependent manner and is required for the normal proliferation, remodeling, and integrity of the vasculature. To better understand the role of Vezfl during vascular development, we propose to study in detail how Vezfl participates in the molecular pathways that control blood vessel formation. We will identify and characterize regulatory regions within the Vezfl gene that are required and sufficient for endothelial, and megakaryocyte specific expression. We will isolate and characterize proteins that functionally interact with these regulatory regions. Finally, we will identify candidate target genes that are regulated by VEZF1.