In several models of angiogenesis, it has been demonstrated that changes in the composition and arrangement of the extracellular matrix of actively growing capillaries correlate with changes in the proliferative, synthetic and ultrastructural properties of their endothelial cells. Recently, numerous in vitro studies have implicated specific components of the extracellular matrix in various aspects of angiogenesis including regulation of endothelial cell phenotype, endothelial cell migration, cell mitosis, organization of cells into capillary-like networks, and regulation of the cell's response to growth factors. Currently, there is little understanding of the specific contribution of individual matrix components to angiogenesis in vivo or the effects of interactions between these components. This study is designed to address these problems and to test the hypothesis that matrix composition helps determine the ultimate fate of a new capillary, be it regression or differentiation and remodelling into an arteriole or venule. Using two models of angiogenesis, the neovascularized rabbit cornea and the developing chick chorioallantoic membrane, the specific aims are to: (1) construct a model of the spatial arrangement of collagen, laminin, proteoglycan and fibronectin in the basal lamina and perivascular extracellular matrix during capillary regression and correlate these changes with the phenotypic characteristics of the endothelial cells; (2) investigate the in vivo role of specific extracellular matrix components in capillary growth and regression by selective inhibition of the biological activity of matrix components and inhibition of their ability to interact with cell surfaces; (3) map the distribution of carbohydrate moieties in growing and regressing capillaries and relate the pattern found to matrix composition, endothelial cell phenotype and the ultimate fate of the blood vessel. These studies will employ light and electron microscopy, histochemistry, immunohistochemistry and autoradiography. Better understanding of the events of angiogenesis in vivo should lead to improved approaches for controlling the adverse consequences of this process in inflammation and in diseases such as neoplasia and diabetes.
| Dethlefsen, S M; Butterfield, C E; Ausprunk, D H (1986) Structural changes induced in capillary endothelial cells by growth factors: altered distribution of cytoskeletal elements and organelles in cells spreading in the presence of tumor conditioned medium and hypothalamus derived growth factor. Tissue Cell 18:827-37 |
