Studies have been initiated to understand the molecular basis of endothelial cell growth regulation. We have isolated from human endothelial cell extracellular matrix a heparan sulfate proteoglycan which binds and potentiates the mitogenic activity of acidic fibroblast growth factor. Our hypothesis states that human endothelial cells synthesize into the extracellular matrix a heparan sulfate proteoglycan which binds and sequester growth factors such as acidic fibroblast growth factor. The extracellular matrix heparan sulfate proteoglycan modulates the mitogenic potential of acidic fibroblast growth factor. The acidic fibroblast growth factor, in turn, controls the synthesis and/or turnover of the extracellular matrix heparan sulfate proteoglycan which binds the growth factors and thus modualtes the interaction of the growth factors with the endothelial cells. The extracellular matrix heparan sulfate proteoglycan, as well as the carbohydrate side chains and the core protein will be isolated and structurally characterized. The structure of the acidic fibroblast growth factor binding region in the extracellular matrix heparan sulfate proteoglycan will be elucidated. In order to determine if the heparan sulfate proteoglycan increases the affinity of acidic fibroblast growth factor for the fibroblast growth factor receptor, the interaction of extracellular matrix heparan sulfate proteoglycan and acidic fibroblast growth factor will be further investigated. The capacity of the isolated extracellular matrix to bind acidic fibroblast growth factor and potentiate endothelial cell growth will be studied. We will evaluate the hypothesis that acidic fibroblast growth factor controls the synthesis and turnover of extracellular matrix heparan sulfate proteoglycan which binds and potentiates the mitogenic activity of acidic fibroblast growth factor. Finally, we will elucidate the structural and functional relationship between the cellular heparan sulfate proteoglycans which binds acidic fibroblast growth factor and the extracellular matrix heparan sulfate proteoglycan which binds acidic fibroblast growth factor. This proposal will test a hypothesis that will provide new information on the growth regulation of human endothelial cells.
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