The extracellular matrix has been found to be important in embryogenesis and in repair. From in vitro studies using purified components, a better understanding of how cells adhere, migrate, proliferate, and differentiate in response to tissue and cell-specific matrix molecules has been established. We have found that the basement membrane, the extracellular matrix which underlies all epithelial cells and endothelial cells and surrounds nerve cells, promotes cell differentiation in vitro. When cultured on basement membrane, endothelial cells form capillary-like structures with a lumen, bone cells form canaliculi, salivary cells form glands, etc. Our goal is to define the molecular and cellular events involved in this process. Our approach has been to identify the (1) biologically active matrix components, (2) localize active sites on the matrix component with site specific antibodies and synthetic peptides, (3) identify and characterize cellular receptors, (4) gain an understanding of the intracellular events involved in the biological response, and (5) identify genes induced by the extracellular matrix. Specifically, we have used the endothelial cell tube forming assay to identify angiogenic factors including scatter factor (hepatocyte growth factor), haptoglobin (which is elevated in vasculitis patients), and estrogens. Estrogens have been found to promote leukocyte adhesion to endothelial cell monolayers via an increase in endothelial cell selectin adhesion receptors. This finding may explain the increase in inflammatory diseases in women. In addition, estrogens promote endothelial cell adhesion, growth and migration. Using the endothelial cell tube assay, a new role for proteases has been defined and may have important clinical uses in vessel repair. Subtractive cDNA cloning of endothelial cells on plastic vs basement membrane has identified several novel genes as well as thymosin B4 and calmodulin as induced during differentiation into vessels. The laminin-derived peptide SIKVAV promotes neurite outgrowth. A brain derived cellular receptor for SIKVAV shares homology with the amyloid precursor protein and may define the role of this protein in development and in Alzheimer's disease.
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