The outgrowth of vascular endothelial cells toward a tumor in the process is an active process that consists of basement membrane degradation, cell migration, cell proliferation and vascular morphogenesis. The motility component is a central requirement of angiogenesis. Directional motility (chemotaxis) is thought to be responsible for directional growth and invasion of vessels as they approach the tumor site whereas random migration (chemokinesis) is thought to be required for vascular branching and anastomosis. The importance of endothelial cell motility is highlighted by the findings that most angiogenic factors, including acidic and basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor/scatter factor (HGF/SF) are potent inducers of microvascular endothelial cell motility whereas a variety of angiogenic inhibitors, including thrombospondin, TNP-470, TIMP 1-3, angiostatin and platelet factor 4 are all potent angiogenic inhibitors. We have begun to investigate the intracellular regulatory elements that control directional cell motility in fibroblasts and epithelial cells in response to the platelet-derived growth factor and we now wish to apply this approach to the motility of microvascular endothelial cells stimulated by angiogenic factors. Our goals are to examine the regulatory elements that control basal and angiogenic factor-stimulated motility with regard to signaling intermediartes. Cytoskeletal elements and focal adhesion components. To inbestigate the differences between directional and random motility in these cells, we wil build on our recent finding that VEGF stimulates directional cell motility whereas basic FGF stimulates random cell motility in endothelial cells. Finally, we will investigate the mechanisms by which known angiogenic inhibitors inhibit endothelial cell motility. This work will be carried out in active collaboration with other members of the progam project team who will provide expertise in growth factor biology (Drs. D'amore and Klagsbrun), in aspects of mechanochemical signaling an focal adhesion dynamics (Dr. Ingber), in cell adhesion (Dr. Bischoff), and in angiogeneiss inhibitors (Drs. Moses and Folkman).
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