The mammalian vascular system develops by two distinct processes, vasculogenesis and angiogenesis. Formation on the vascular system during embryogenesis from the lateral plate mesoderm and the extra embryonic mesoderm of the visceral folk sac is under complex genetic control, as suggested by the identification of a number of mutations in mice that affect its development. We have identified a novel gene, Zezf1, that we hypothesize is a key regulator of these processes. The gene, identified using retroviral entrapment vectors in murine ES cells, encodes a protein consisting of six zinc finger domains and is homologous to the human transcription factor, DB1. During embryogenesis, Vezf1 is expressed specifically in vascular endothelial cells, the cells that line the blood vessels, and in their precursors in the yolk sac blood islands. In adults, Vezf1 expression is primarily confined in the quiescent vascular endothelium, but is strongly up-regulated during angiogenesis and in response to vascular injury. The goal of this proposal is to understand the role of Vezf1 during blood vessel development. This will be accomplished using gain-of function and loss of function studies. Wild-type and dominant-negative mutants of Vezf1 will be generated and their effects in ES cells and on vasculogenesis and angiogenesis in transgenic mice will be investigated. In addition, the Vezf1 gene will be knocked-out in ES cells and in mice to study the consequences of its loss on these processes. Specifically, we will: 1. Investigate the function of VEZF1 as a transcription factor. 2. Determine the role of Vezf1 in vasculogenesis and angiogenesis using transgenic mice expressing gain-of function and dominant-negative mutations of Vezf1. 3. Determining the consequences of the loss of Vezf1 on mouse development using Vezf1 knock-out mice. These results will impact our understanding of the molecular mechanisms governing normal and abnormal processes of vasculogenesis and angiogenesis. These include congenital cardiovascular abnormalities and pathological conditions such as rheumatoid arthritis, retinopathies, hemangiomas, psoriasis, solid tumors and metastases.
