Endothelial shear stress (ESS) is proportional to the product of the blood viscosity (µ) and the spatial gradient of blood velocity at the wall (dv/dy).

Schematic figure illustrating the characteristics of flow patterns. (A) Undisturbed laminar flow is a smooth streamlined flow chacterized by concentric layers of blood moving in parallel along the course of the artery; (B) disturbed laminar flow is characterized by reversed flow (i.e., flow separation, recirculation, and reattachment to forward flow); (C) in turbulent flow the blood velocity at any given point varies continuously over time, even though the overall flow is steady. Adapted from Munson et al. (28). Re = Reynolds number.

Definition of pulsatile, low, and oscillatory endothelial shear stress (ESS). Adapted from Ku et al. (10).

Local endothelial shear stress (ESS) is sensed by luminal endothelial mechanoreceptors, such as ion channels (K⁺, Ca²⁺, Na⁺, Cl^–), G-proteins, caveolae, tyrosine kinase receptors (TKRs), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase (XO), plasma membrane lipid bilayer, and heparan sulfate proteoglycans. Also, ESS signals are transmitted through the cytoskeleton to the basal or junctional endothelial surface, where certain integrins or a mechanosensory complex consisting of platelet endothelial cell adhesion molecule-1 (PECAM-1) and Flk-1 are activated, respectively, and initiate a downstream signaling cascade. Activated integrins phosphorylate and activate a multiple complex of non-receptor tyrosine kinases (FAK, c-Src, Shc, paxillin, and p130^CAS), adaptor proteins (Grb2, Crk), and guanine nucleotide exchange factors (Sos, C3G), thereby activating Ras family GTPase. Active Ras plays a pivotal role in intracellular transduction of ESS signals as it triggers various parallel downstream cascades of serine kinases; each of these kinases phosphorylates and hence activates the next one downstream, ultimately activating mitogen-activated protein kinases (MAPKs). Besides integrin-mediated mechanotransduction, ESS activates a number of other downstream signaling pathways initiated by luminal or junctional mechanoreceptors. These pathways include the production of reactive oxygen species (ROS) from NADPH oxidase and XO, activation of protein kinase C (PKC), activation of Rho family small GTPases (which mediate the remodeling cytoskeleton resulting in temporary or permanent structural changes of ECs), release of endothelial nitric oxide synthase (eNOS) and other signaling molecules from caveolae, and activation of phosphoinositide-3 kinase (PI3K)-Akt cascade. Ultimately, all of these signaling pathways lead to phosphorylation of several transcription factors (TFs), such as nuclear factor-kappa ß (NF-B) and activator protein-1 (AP-1). These TF proteins bind positive or negative shear stress responsive elements (SSREs) at promoters of mechanosensitive genes inducing or suppressing their expression, thereby modulating cellular function and morphology.

The endothelial cytoskeleton transmits the shear forces to the focal adhesions located at the basal endothelial surface, where a downstream intracellular signaling cascade starts. The shear forces can also be transmitted to mechanoreceptors at the cell–cell junctions, luminal surface, and nucleus (N). Adapted from Davies et al. (45). ESS = endothelial shear stress.

In arterial regions with disturbed laminar flow, low endothelial shear stress (ESS) shifts the endothelial function and structure toward an atherosclerotic phenotype, thereby promoting atherogenesis, atherosclerotic plaque formation and progression, and vascular remodeling. BMP = bone morphogenic protein; ET = endothelin; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; LDL = low-density lipoprotein cholesterol; MCP = monocyte chemoattractant protein; MMP = matrix metalloproteinase; NO = nitric oxide; PDGF = platelet-derived growth factor; SREBP = sterol regulatory elements binding protein; TF = transcription factor; TGF = transforming growth factor; TNF = tumor necrosis factor; t-PA = tissue plasminogen activator; VCAM = vascular cell adhesion molecule; VEGF = vascular endothelial growth factor; VSMC = vascular smooth muscle cell; other abbreviations as in Figure 4.

The initiating process of atherosclerosis in an atherosclerosis-prone host is a low endothelial shear stress (ESS) environment, leading to the formation of an early fibroatheroma, which might be diffuse. The vascular response to that early fibroatheroma likely determines the nature of the subsequent natural history of that plaque. If there is local compensatory expansive remodeling, then the local ESS is normalized, the hemodynamic stimulus for further plaque progression is resolved, and the early lesion evolves to a quiescent plaque with limited inflammation. However, in the presence of certain local, systemic, and genetic factors, the local vascular wall might undergo excessive expansive remodeling. In this context the local low ESS environment persists, promoting further plaque progression and vessel expansion. A self-perpetuating vicious cycle is established among local low ESS, excessive expansive remodeling, and plaque inflammation, transforming the early fibroatheroma to a thin cap fibroatheroma. The stenotic plaques might either evolve with a phenotype promoting fibroproliferation consistently throughout their natural history course or represent an end-stage of scarring in the setting of prior inflamed thin cap fibroatheroma through repetitive microruptures and healing. Also, the stenotic plaques might infrequently undergo local erosion or develop calcified nodules and lead to local thrombus formation and manifestation of an acute coronary syndrome. The percentages reported in the figure are based on intravascular ultrasound studies (23,110,111).

(A) Example of a 3-dimensional (3D) reconstructed coronary arterial segment. (B) Example of endothelial shear stress (ESS) profiling along a 3D reconstructed left anterior descending artery. Panel A was adapted from Stone et al. (15). Pa = Pascal.