The role of shear stress in the pathogenesis of atherosclerosis

Abstract

Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis. Laboratory Investigation (2005) 85, 9-23, advance online publication, 29 November 2004; doi:10.1038/labinvest.3700215Keywords: shear stress; atherosclerosis; endothelium; smooth muscle cells; nitric oxide; cytoskeleton; mechanotransductionThe parallel frictional drag force of shear stress is one of the important blood flow-induced mechanical stresses acting on the vessel wall, which also includes the perpendicular force of blood pressure and the cyclic stretch of pulsatile flow. Shear stress is a biomechanical force that is determined by blood flow, vessel geometry and fluid viscosity that is computationally estimated using fluid dynamics models and is expressed in units of dynes/cm 2 .

Shear stress stimulates phosphorylation of protein kinase A substrate proteins including endothelial nitric oxide synthase in endothelial cells

“…As shown in Figure 6, P135 was imunoprecipitated by monoclonal eNOS antibody but not by non-immune IgG. The same band was detected when probed with either eNOS antibody or the pospho-PKA substrate antibody, identifying P135 as eNOS, which is known to mediate atheroprotective effect of laminar shear stress (Traub and Berk, 1998;Resnick et al, 2003;Cunningham and Gotlieb, 2005).…”

“…Shear stress regulates vascular tone and diameter, inflammatory responses, hemostasis, vessel wall remodeling and other vascular functions (Resnick et al, 2003). Laminar shear stress has been proposed to play anti-atherogenic roles by inhibiting some of the key pro-atherogenic events including apoptosis of endothelial cells and binding of monocytes to endothelium (Cunningham and Gotlieb, 2005). Various receptors present on the surface of endothelial cells and other mechanosensing machinery allow vessels to detect subtle changes in shear stress (Davies, 2002;Dusserre et al, 2004;Fleming et al, 2005).…”

The effects of shear flow on protein structure and function

“…96 Arterial shear rates peak at 1640 s 21, 96 reaching 10 4 s 21, 58 in partly clogged coronary arterioles. The literature contains a significant number of reports [98][99][100][101][102][103][104][105][106][107] (and references therein) linking the haemodynamic stress generated on arterial walls during microcirculation, specifically in regions of relatively low shear stress, to the pathogenesis of atherosclerosis through the modulation of endothelial function. 108 A characteristic hallmark of this disease state is the deposition of amyloidlike protein aggregates as plaque on arterial walls.…”

Flow-Mediated Vasodilation in End-Stage Renal Disease

“…Physiologic laminar fluid shear stress (SS), the product of shear rate (SR) and whole blood viscosity (WBV), applied to endothelial cells is responsible for endothelial cell survival and quiescence (1,2). Under physiologic conditions, SS is the principal mechanostimulus modulating vascular tone, through releasing endothelial-derived relaxing factors (nitric oxide [NO], prostacyclin, hyperpolarizing factors) associated with flow-mediated dilation (FMD).…”