Atherosclerosis, the leading cause of death in the developed world and
nearly the leading cause in the developing world, is associated with systemic
risk factors including hypertension, smoking, hyperlipidemia, and diabetes
mellitus, among others. Nonetheless, atherosclerosis remains a geometrically
focal disease, preferentially affecting the outer edges of vessel bifurcations.
In these predisposed areas, hemodynamic shear stress, the frictional force
acting on the endothelial cell surface as a result of blood flow, is weaker
than in protected regions. Studies have identified hemodynamic shear stress
as an important determinant of endothelial function and phenotype. Arterial-level
shear stress (>15 dyne/cm2) induces endothelial quiescence and
an atheroprotective gene expression profile, while low shear stress (<4
dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates
an atherogenic phenotype. The functional regulation of the endothelium by
local hemodynamic shear stress provides a model for understanding the focal
propensity of atherosclerosis in the setting of systemic factors and may help
guide future therapeutic strategies.

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Hemodynamic shear stress and its role in atherosclerosis.

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.

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

Mechanical forces are important modulators of cellular function in many tissues and are particularly important in the cardiovascular system. The endothelium, by virtue of its unique location in the vessel wall, responds rapidly and sensitively to the mechanical conditions created by blood flow and the cardiac cycle. In this study, we examine data which suggest that steady laminar shear stress stimulates cellular responses that are essential for endothelial cell function and are atheroprotective. We explore the ability of shear stress to modulate atherogenesis via its effects on endothelial-mediated alterations in coagulation, leukocyte and monocyte migration, smooth muscle growth, lipoprotein uptake and metabolism, and endothelial cell survival. We also propose a model of signal transduction for the endothelial cell response to shear stress including possible mechanotransducers (integrins, caveolae, ion channels, and G proteins), intermediate signaling molecules (c-Src, ras, Raf, protein kinase C) and the mitogen activated protein kinases (ERK1/2, JNK, p38, BMK-1), and effector molecules (nitric oxide). The endothelial cell response to shear stress may also provide a mechanism by which risk factors such as hypertension, diabetes, hypercholesterolemia, and sedentary lifestyle act to promote atherosclerosis.

Laminar Shear Stress Mechanisms by Which Endothelial Cells Transduce an Atheroprotective Force

Molecular basis of the effects of shear stress on vascular endothelial cells.

—Low and oscillatory shear stresses are major features of the hemodynamic environment of sites opposite arterial flow dividers that are predisposed to atherosclerosis. Atherosclerosis is a focal inflammatory disease characterized initially by the recruitment of mononuclear cells into the arterial wall. The specific characteristics of the hemodynamic environment that facilitate the generation of arterial inflammatory responses in the presence of, for example, hyperlipidemia are unknown. We show here that prolonged oscillatory shear stress induces expression of endothelial cell leukocyte adhesion molecules, which are centrally important in mediating leukocyte localization into the arterial wall. Vascular cell adhesion molecule-1 was upregulated an average 9-fold relative to endothelial monolayers in static culture. Intercellular adhesion molecule-1 and E-selectin exhibited 11-fold and 7.5-fold increases, respectively. Upregulation of these adhesion molecules was associated with enhanced monocyte adh...

Oscillatory Shear Stress Stimulates Adhesion Molecule Expression in Cultured Human Endothelium

Vascular endottielial cell proliferation in culture and the influence of flow

The influence of hydrodynamic forces on anchorage-dependent mammalian cells is of interest both in biomedical research and in the development of scaled-up mammalian cell bioreactor systems. Our own studies, reviewed here, have demonstrated that, in response to a fluid-imposed laminar shear stress, cultured vascular endothelial cells undergo a dramatic alteration in structure and function. From these and related studies, it may be possible to obtain some insight into the general response of anchorage-dependent mammalian cells to hydrodynamic forces. An unanswered question is: how does such a cell recognize and then transduce a fluid mechanic signal?

M. J. Levesque

Papers

Vascular endottielial cell proliferation in culture and the influence of flow

The Influence of Shear Stress on Cultured Vascular Endothelial Cells: The Stress Response of an Anchorage-Dependent Mammalian Cell