Shear Stress–Initiated Signaling and Its Regulation of Endothelial Function

Abstract

Atherosclerosis develops preferentially at branches and curvatures of the arterial tree, where blood flow pattern is disturbed rather than being laminar, and wall shear stress has an irregular distribution without defined directions. The endothelium in the atherosusceptible regions, in comparison to that in atheroresistant regions, shows activation of pro-proliferative and pro-inflammatory gene expressions, reduced production of nitric oxide (NO), increased leukocyte adhesion and permeability, as well as other atheroprone phenotypes. Differences in gene expressions and cell phenotypes have been detected in endothelia residing in native atherosusceptible and atheroresistant regions of the arteries, or in arteries from animal models with artificial creation of disturbed flow. Similar results have also been shown in in vitro systems that apply controlled shear stresses with or without clear directions to cultured endothelial cells (ECs) in fluid-dynamically designed flow-loading devices. The available evidence indicates that the coordination of multiple signaling networks, rather than individual separate pathways, link the mechanical signals to specific genetic circuitries in orchestrating the mechanoresponsive networks to evoke comprehensive genetic and functional responses.

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

“…Although ICAM-1 expression showed a milder induction than VCAM-1, av siRNA completely suppressed Although acute onset of flow provides an easily reproducible model for shear stress signaling, endothelial cells at atherosclerosis-prone sites in vivo are chronically exposed to disturbed flow patterns. To determine whether integrinspecific signaling similarly regulates the chronic inflammation seen in disturbed flow models, a5 and av knockdown HAECs were exposed to oscillatory shear stress (model of disturbed flow 2,8 ) for 18 hours. Similar to the onset of flow, knockdown of av integrins but not a5 integrins inhibited flowinduced VCAM-1 ( Figure 3G) and ICAM-1 protein expression ( Figure 3H).…”

“…Although traditional risk factors for atherosclerosis, such as hypercholesterolemia and hyperglycemia, are systemic throughout the circulation, atherosclerotic plaques form at discrete areas of the vasculature where vessel geometry results in altered hemodynamics. 1,2 Endothelial cells respond to the frictional force generated by these flow patterns, termed shear stress, and convert them into intracellular biochemical signals that critically modulate endothelial cell function. In straight regions of arteries, shear stress generated by unidirectional, laminar flow promotes nitric oxide production and limits endothelial cell activation, consistent with the absence of atherosclerosis in these areas.…”

“…In straight regions of arteries, shear stress generated by unidirectional, laminar flow promotes nitric oxide production and limits endothelial cell activation, consistent with the absence of atherosclerosis in these areas. 1,2 In contrast, shear stress generated by disturbed flow patterns, such as those observed at sites of vessel branch points, bifurcations, and curvatures, results in endothelial cell activation with enhanced proinflammatory gene expression [intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1)] and permeability. 1,2 In addition to flow patterns, cell matrix interactions can also affect local endothelial cell activation.…”

“…1,2 In contrast, shear stress generated by disturbed flow patterns, such as those observed at sites of vessel branch points, bifurcations, and curvatures, results in endothelial cell activation with enhanced proinflammatory gene expression [intercellular adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1)] and permeability. 1,2 In addition to flow patterns, cell matrix interactions can also affect local endothelial cell activation. Endothelial cells typically reside on basement membrane proteins (ie, collagen IV and laminin), which resist endothelial cell activation and promote a quiescent phenotype.…”

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

“…In the straight part of the arteries, endothelial cells (ECs) are exposed to laminar blood flow with high shear stress that protects these parts of the vessels from atherogenesis, whereas in the branches and curvatures, the ECs experiencing disturbed flow with reciprocating and low shear stress stimulate the smooth muscle cells (SMCs) within the tunica media to become proliferative and migratory. The activated SMCs migrate into the intima, where they come into close contact with ECs and undergo phenotypic changes to lead to atherosclerosis (2). We recently demonstrated that vascular ECs repress expressions of forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 in the adjacent SMCs by producing microRNA-126-3p (miR-126-3p), and hence induce SMC turnover, and that the application of atheroprotective laminar shear (LS) at 12 dynes/cm 2 to ECs inhibits this paracrine effect (3).…”