Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives

Jeng-Jiann Chiu, Shu Chien


Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.

  • Abbreviations:
    Complex flow patterns
    The patterns of flow that are difficult to characterize; they can be made of many different types of flow such as disturbed flow, reciprocating flow, recirculation eddy, flow separation and reattachment, etc.
    Cyclic stretch
    Periodic lengthening of elements in the vessel wall in the circumferential direction produced by periodic increases in transmural pressure difference, or periodic lengthening of the cultured endothelial cells in one direction (uniaxial cyclic stretch) or all directions (biaxial cyclic stretch).
    Disturbed flow
    The pattern of flow that is nonuniform and irregular, including recirculation eddies and changes in direction with time (reciprocating flow) and space (flow separation and reattachment).
    Flow reattachment
    After flow separation, the part of the flow that forms the boundary between the recirculating flow and the forward flow through the central region of the tube (vessel) is called the dividing streamline. The point at which the dividing streamline attaches to the wall again is called the flow reattachment point, where the velocity gradient and shear stress vanish to become zero.
    Flow separation
    The boundary layers of flow that separate from the surface of the vessel wall to form a recirculation eddy behind the separation point, where the velocity gradient and shear stress vanish.
    Fluid shear stress
    The tangential component of frictional forces generated at a surface (e.g., the vessel wall) by the flow of a viscous fluid (e.g., blood). The unit for shear stress is Pascal (Pa) in the SI system (the International System of Units). In the cardiovascular system, dyn/cm2 is usually used: 1 Pa = 10 dyn/cm2. The “shear stress” used in this article denotes wall shear stress unless otherwise stated.
    Hydrostatic pressure
    The pressure exerted by a fluid at equilibrium due to the force of gravity.
    Laminar flow
    A well-ordered pattern of streamlined flow that occurs when a fluid flows in parallel layers, with friction between the successive layers.
    Pulsatile flow
    Periodic flow with a positive mean flow rate; the velocity of the fluid oscillates in time at the frequency of the periodicity with a significant net direction.
    Reciprocating flow
    Periodic flow with little mean flow rate; the velocity of the fluid oscillates in time mainly back and forth at the frequency of the periodicity.
    Recirculation eddy
    Swirling of a fluid with reverse streamlines created when the fluid flows past an obstacle, a curvature, or a region with diameter change.
    The reflux in the venous system is defined as a pathophysiological retrograde (distally directed) flow in an incompetent vein that occurs between the veins in the thigh and the lower leg of an individual in an erect position and under the influence of gravitation.
    Retrograde flow
    The flow of fluid in a direction other than the physiological direction, as in reflux.
    Step flow
    The flow over a backward-facing step, which is achieved in the cone-and-plate viscometer by imposing a rectangular obstacle or in the parallel-plate flow chamber by using two silicone gaskets with the top one having a longer longitudinal cutout than the one below (Fig. 8). This flow is comprised of a well-defined recirculation eddy immediately downstream of the step, followed by a region of flow reattachment, and finally with a unidirectional laminar flow that is reestablished further downstream (Fig. 9).
    Turbulent flow
    Flow in which the velocity at any given point varies continuously over time, even though the overall flow may be steady. In turbulent flow, the inertial forces are more significant than viscous forces; it begins to be significant when the Reynolds number (flow velocity × fluid density × vessel diameter/fluid viscosity) exceeds a critical level; this critical Reynolds number becomes lower with an increase in complexity of vascular geometry. Turbulent blood flow is uncommon in normal circulation, but it occurs in human aorta at peak systole (especially during heavy exercise), in arteries distal to severe stenoses, and in aneurysms.
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