Role of fibronectin in vascular plexus self-organization during embryogenesis

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DESCRIPTION (provided by applicant): Vessel formation from mesodermal progenitors, vasculogenesis, is a fundamental process common to both embryonic development and certain pathophysiologies. Recently we showed that the formation of vascular cords from isolated clusters of angioblasts involves extensive invasive activity. During this process, vasculogenic sprouting, a group of endothelial cells invades hundreds of micrometers into avascular areas, and thereby lays down the structure of the primordial vascular plexus. We aim to determine the specific role of fibronectin, and its major endothelial receptors in the process. Specifically, we will (1) determine if fibronectin acts as a guidance cue during vasculogenic sprouting, (2) study the cell-mediated macro- assembly dynamics and turnover of the transient, fibronectin-rich extracellular matrix surrounding the cords of primordial endothelial cells, (3) determine the molecular composition of cell adhesion complexes and the respective roles of integrins avb3 and a5b1, and (4) synthesize the experimental data into a quantitative model of vasculogenesis. Vasculogenic sprouting will be studied in vivo, through automated optical microscopy and a combination of fluorescence-tagged antibodies and GFP constructs, in the presence or absence of perturbing reagents. The long term goal of the project is to understand endothelial cell-ECM interactions in sufficient detail to allow the construction of predictive quantitative models, either for tissue engineering, or to understand developmental morphogenetic processes. Understanding blood vessel development is of overwhelming clinical importance. Our goal, and the goal of other vascular biologists, is to explain the mechanisms that promote or inhibit vessel growth and thus regulate the structure of the vessel network. In particular, endothelial progenitors are in the focus of therapeutic vascularization strategies, tissue engineering, and attempts to block tumor growth.