Hemodynamic Forces and the Endothelium

Shear Stress

Blood flow through a vascular segment generates a viscous drag at the luminal surface of endothelial cells (Figure 3), which can be expressed as shear stress (t) and calculated according to Poiseuille's law:

(where h = viscosity, Q = blood flow, r = internal vessel radius).

This relation highlights the fact that relatively small decreases in vessel diameter at constant flow can markedly increase shear stress at the endothelial surface. It should be noted, however, that shear stress is calculated under the assumption that the flow profile is parabolic, a situation that is never realized in vivo because of the pulsatile nature of blood flow and the fact that blood vessels are distensible. Branching and bifurcations along the vascular tree together with a gradual decrease in diameter also disfavor the establishment of a stable flow profile.

Pulsatile Stretch/Cyclic Strain

Although it is sometimes assumed that pressure per se is a proper physiological stimulus for the vascular wall, it must be emphasized that the application of pressure in the physiological range (below 1 atm) to a tissue that is essentially incompressible because of its high water content has no direct effect on cell function. Rather, the pressure exerted on a compliant tissue elicits deformation, that is, either distension (stretch) or compression. As a result of pulsatile pressure changes, cells within the vascular wall are subjected to three-dimensional cyclic strain in the radial, longitudinal, and circumferential directions. There are also cell-cell-generated forces that are influenced by hemodynamic stimuli but that cannot be expressed by a simple physical relationship. One example is the isometric contraction in which the development of contractile force within the smooth muscle cell layer counteracts the distending transmural pressure. Under such conditions there is a relative displacement of opposing cell layers within the vascular wall (e.g., smooth muscle cells versus elastic lamina and endothelial cells), despite the fact that no net movement occurs. Although the displacement induced may be subtle, the close physical arrangement of endothelial focal adhesion contacts and the smooth muscle would tend to suggest that the forces developed at the abluminal surface of endothelial cells may be greater than those generated by shear stress on the luminal surface.

In principle, the relative contribution of pulsatile stretch and wall shear stress to the adjustment of local vascular tone is likely to depend on a number of factors including vessel

Figure 3 Scheme illustrating the hemodynamic forces affecting endothelial cells. Note that, because of the pulsatile nature of flow, the flow profile is flattened compared to the parabolic flow profile present under steady-state conditions, resulting in a greater shear stress at the endothelial cell surface. The simultaneous pressure (P) pulse distends the vessel diameter (D) and stretches endothelial cells in the range of 1-5% strain. These stimuli result in a redistribution of force across the endothelial cell cytoskeleton and the activation of signaling molecules (including integrins) at the abluminal and luminal cell surfaces as well at sites of cell-cell contact. Adapted from Busse, R., and Fleming, I. (2003). Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol. Sci. 24, 24-29, reprinted with permission from Elsevier Science Ltd. (see color insert)

Figure 3 Scheme illustrating the hemodynamic forces affecting endothelial cells. Note that, because of the pulsatile nature of flow, the flow profile is flattened compared to the parabolic flow profile present under steady-state conditions, resulting in a greater shear stress at the endothelial cell surface. The simultaneous pressure (P) pulse distends the vessel diameter (D) and stretches endothelial cells in the range of 1-5% strain. These stimuli result in a redistribution of force across the endothelial cell cytoskeleton and the activation of signaling molecules (including integrins) at the abluminal and luminal cell surfaces as well at sites of cell-cell contact. Adapted from Busse, R., and Fleming, I. (2003). Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol. Sci. 24, 24-29, reprinted with permission from Elsevier Science Ltd. (see color insert)

architecture, moment-to-moment changes in smooth muscle activity, and the ability of endothelial and smooth muscle cells to sense hemodynamic stimuli and to produce vasoactive factors. Although it is tempting to break down hemodynamically generated forces into singular physical components such as circumferential stretch/strain and wall shear stress, it must be emphasized that such a procedure is purely theoretical, as changes in pulsatile stretch and shear stress are inextricably linked.

Mechanochemical Coupling

The term mechanochemical coupling describes how endothelial cells translate physical stimuli into intracellular signals and ultimately into changes in autacoid production. Initially, one or more mechanoreceptors were suggested to sense changes in fluid shear stress at the endothelial cell surface; however, the endothelial cell cytoskeleton itself can be regarded as a mechanoreceptor. The cytoskeletal frame of an endothelial cell is composed of actin filaments, intermediate filaments, and microtubules that transverse the cells and end in characteristic adhesion complexes at the luminal cell surface (caveolae), at the abluminal surface (focal adhesion points), or at cell-cell boundaries. Signaling molecules are clustered around and inherent in these sites so that it is conceivable that fluid shear stress acting on the luminal surface of the endothelial cell is transmitted through the entire cell by the cell cytoskeleton to activate signal transduction cascades in specific signaling hot spots.

Other possible mechanisms by which endothelial cells may sense shear stress are through mechanosensitive ion channels and the glycocalyx, a layer of glycoproteins extending into the extracellular space, which may be displaced by shear stress to elicit an intracellular response. Alternatively, flow induces changes in the concentrations of endothelial agonists (e.g., ATP, ADP, and bradykinin) in the unstirred boundary layer at the cell surface, and thus may affect intracellular signaling pathways.

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