Embryonic blood vessels formation involves two processes, vasculogenesis and angiogenesis, that occur simultaneously in different embryonic locations. The endothelial cell is critical to both processes, since vasculogenesis involves the in situ differentiation of endothelial cells and angiogenesis occurs by the migration of sprouts of endothelial cells from pre-existing vessels. However, an endothelial precursor, called the angioblast, is poorly characterized in the mouse and it is unknown how a subset of angioblasts that are highly invasive and migratory as single cells contribute to vascular development. The experiments proposed in this competitive renewal application will focus on a more complete characterization of the murine angioblast and examine the hypothesis that mouse angioblasts respond to patterning signals via receptor tyrosine kinases. The investigator will use mouse models that she has developed, including an in vitro model of vascular development. Differentiation of ES cells mutant for VEGF or the VEGF receptor, flt-1, will help clarify the role of VEGF/receptor signaling in early vascular development. The somite provides a defined unit of embryonic tissue that can be manipulated and has vascular potential. Thus, the investigator proposes to investigate the properties of somite-derived angioblasts in the mouse, by explant culture and a novel procedure for the transfer of somites between mouse embryos. The incorporation of targeted mutations in vascular-expressed receptor tyrosine kinase genes into these analyses should permit an assessment of the effects of specific molecular interactions on angioblast function and maturation. Finally, the ability of axial structures to influence vascular development will be investigated by co-culture explant experiments and analysis of mouse mutants with defective axial structures. It is anticipated that these studies will provide a more complete understanding of vascular development in the mammal. Because many pathologies result from, or are accompanied by inappropriate blood vessel formation in the adult, a better understanding of developmental processes will help determine to what extent these processes participate in pathologic neovascularization. Specifically, if migratory angioblasts participate in embryonic angiogenesis, they may, by analogy also participate in disease-related angiogenesis.
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