We are using transgenic fli1-gfp zebrafish to model angiogenesis in living embryos. In the fli1-gfp transgene the promoter from the fli1 gene drives expression of the Green Fluorescent Protein (GFP) in all endothelial cells. This allows the migration of endothelial cells and development of blood vessels to be followed in living embryos by examination under the microscope with epifluorescence illumination. We can also easily observe defects in these processes. Angiogenesis in the zebrafish embryo begins after the first day of development. During this time the intersegmental vessels in the trunk develop from the dorsal aorta in the first wave of embryonic angiogenesis. We are currently measuring the rate of endothelial cell migration during angiogenesis in the fli1-gfp transgenic embryos and how the rate of migration is affected by different concentrations of VEGF. Previous work suggests a link between VEGF and Syndecan-2, which may function as a co-receptor for VEGF. To investigate this possible connection, we are using an antisense technology to inhibit the expression of VEGF and Syndecan-2 in the embryo and characterizing antibodies to measure VEGF and Syndecan-2 levels. We are currently developing equations that include terms expressing reaction, diffusion, and cell movement biased by "convection" like terms to model this interaction. These terms model the chemotactic influences on cells, and hence the interaction of the cells with the extracellular matrix that results in their directed movement towards the diffusible growth factor. Using this approach as a framework, we expect to develop mathematical models for angiogenesis for zebrafish that are both predictive and descriptive of growth factor signaling and extracellular matrix interactions during cell migration. Based on the high degree of conservation of signaling pathways involved in angiogenesis, we expect that modeling these processes in zebrafish will be directly applicable to tumor angiogenesis.
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