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Chapter 6: MOLECULAR AND CELLULAR BIOLOGY OF BLOOD VESSELS ENDOTHELIAL RESPONSES TO HEMODYNAMIC INFLUENCES
In addition to being influenced by the interaction of circulating blood cells, VSMCs, and matrix, the endothelium responds to the physical forces of pressure, stretch, and shear stress imposed by the hemodynamics of the circulation. Flow-mediated, endothelium-dependent vasodilation has been described in many vascular beds,425 and shear stress has been proposed to play a role in controlling endothelial cell proliferation.!26 Elevated pressure, stretch of the vessel wall, and shear stress have all been shown independently to affect endothelial cell morphology and/or function. Pressure alone appears to have a role in the generalized hypertrophy of the vessel wall that occurs during hypertension. Studies in cultured cells have shown that stretching endothelial cells leads to changes in cell shape, intracellular signal generation with an increase in calcium concentration, and proliferation.126 Shear stress has numerous effects on endothelial cells. Initially, it was found that exposure of endothelial cell monolayers to elevated shear stresses in vitro caused them to align in the direction of flow. This reorientation was accompanied by changes in the cytoskeleton of the cells, including reorganization and alignment of the actin filaments and microtubules (Q-hB; Fig. 6-6). Similar mechanisms presumably also account for the orientation of endothelial cells parallel to the longitudinal axis in areas of laminar flow in the arterial system. The function of endothelial cells is also altered by shear stress: a K+ current is activated; secretion of vasoactive and growth factors, including NO, endothelin, prostacyclin, and basic FGF (bFGF) is increased; tissue factor expression is increased; uptake of LDL is elevated; and tPA secretion is increased.126
The importance of these observations lies in the variation in hemodynamic forces throughout the circulation. High pressure, such as that which occurs in hypertension, causes changes in the morphology and function of the vessel wall.!27 In addition, the areas of the vasculature exposed to low shear stress (branch points and curvatures) exhibit a predilection to the formation of atherosclerotic lesions.!28 It is thus clear that the hemodynamic environment of the endothelium and underlying smooth muscle is a potentially powerful regulator of vascular function.
The mechanism(s) by which the endothelial cell can sense and transduce mechanical signals has not been defined definitively. Possibilities include signaling through focal adhesion complexes, a surface mechanoreceptor, a flow-sensitive ion channel, changes in cytoskeletal stress due to deformation, and flow-dependent gradients of bioactive substances along the surface of the cell. Recent data have implicated heterotrimeric G-protein activation.!29 Furthermore, caveolae, which are budding, membrane vesicular structures as described previously, are rich in signaling molecules such as G proteins and may be involved in signal generation in response to shear stress.!30
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