Molecular Biological and Bio-Engineering Study of Blood Flow-Sensing and Responding Mechanism of Vascular Endothelial Cells.

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The hemodynamic force of blood flow is speculated to modulate endothelial cell functions and play an important role in the regulation of the structure of the vessel and in the initiation of early lesions of atherosclerosis. To prove this hypothesis, we studied how vascular endothelial cells recognize the hemodynamic changes in blood flow and modulate their functions. By using a flow-loading apparatus hydrodynamically designed in our laboratory, we applied fluid flow to cultured vascular endothelial cells, and studied the changes in cytoplasmic free calcium ion concentrations, ability of endothelial regeneration, DNA synthesis, production and secretion of collagen, and release of endothelium-derived relaxing factor (EDRF). The results obtained were as follows : 1) Application of medium flow to endothelial cells induced a transient rise in cytoplasmic calcium concentrations. The flow-inducedcalcium response needed the presence of ATP in perfusion fluids and, especially at 500 nM ATP, end … More othelial cells showed the gradual increase in calcium concentrations in response to the gradual increase in flow (shear stress ranging from 0 to 42 dyn/cm^2), indicating that endothelial cells perceive flow (shear stress) as a stimulus via a second messenger, calcium ion. 2) Application of flow yielding shear stress of 1-3 dyn/cm^2 for 24-48 hours stimulated endothelial cell migration and proliferation during regeneration after mechanical denudation. Cell migration occurred downstream prominently. Flow application also enhanced DNA synthesis by endothelial cells during regeneration and increased the percentage of the cells locating in the mitotic phase of the cell cycle. Furthermore, endothelial cells reacted to flow to produce stimulators of smooth muscle cell migration. Endotial cells produce collagen, an extracellular matrix, and EDRF which relaxes smooth muscle cells and inhibits platelets aggregation, and these functions were stimulated by flow application. It was also observed that the flow-induced release of EDRF by endothelial cells relate to the flow-induced calcium transients. Less