Mechanotransduction of shear in the endothelium: Basic studies and clinical implications

Abstract

The endothelium plays an integral role in the development and progression of atherosclerosis. Hemodynamic forces, particularly shear stress, have a powerful influence on endothelial phenotype and function; however, there is no clear consensus on how endothelial cells sense shear. Nevertheless, multiple endothelial cell signal transduction pathways are activated when exposed to shear stress in vitro. The type of shear, laminar or oscillatory, impacts which signal transduction pathways are initiated as well as which subsequent genes are up- or down-regulated, thereby influencing endothelial phenotype and function. Recently, human studies have examined the impact of shear stress and different shear patterns at rest and during exercise on endothelial function. Current evidence supports the theory that augmented exercise-induced shear stress contributes to improved endothelial function following acute exercise and exercise training, whereas retrograde shear initiates vascular dysfunction. The purpose of this review is to examine the current theories on how endothelial cells sense shear stress, to provide an overview on shear stress-induced signal transduction pathways and subsequent gene expression, and to review the current literature pertaining to shear stress and shear patterns at rest as well as during exercise in humans and the related effects on endothelial function.

Exercise and Atherosclerotic Cardiovascular Disease

“…The manner in which this occurs is incompletely understood, but hemodynamic forces, particularly shear stress, are known to exert a powerful influence on EC phenotype and function, and likely play a major role in the atheroprotective effects of exercise [30].…”

“…The resultant change in endothelial phenotype is dependent on the type of shear stress. Laminar blood flow produces predominantly antegrade shear stress along the EC surface which favors an atheroprotective EC phenotype, whereas retrograde, oscillatory and slow shear stress of the type that occurs at bifurcations in the arterial tree predispose to an atherogenic EC phenotype [30].…”

“…An early event in atherogenesis is the activation of ECs in response to the injurious effects of glycated or oxidized LDL, oscillatory or diminished levels of shear stress, infection with agents such as CMV, HIV-1, or Chlamydia pneumoniae, free radicals arising during oxidative stress, heat shock protein 60, hypertension, cigarette smoking and/or inactivity [10,16,[29][30][31][32][33][34][35]. Activated ECs upregulate their production of chemokines, adhesins, VSMC growth and activation factors, and downregulate their production of TGF-β, vasodilators, antioxidants, and anticoagulants.…”

Goal Function Approach to Growth and Remodeling of Arteries

“…Blood that flows through the vessel shears the endothelium of the vessel wall. Mechanoreceptors on the surface of the endothelial cells sense the shear stress, and through a cascade of molecular signals, the surrounding cells react and the vessel adapts its diameter to the new level of blood flow [9,10,11].…”

Heparan Sulfates Mediate the Interaction between Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) and the Gαq/11 Subunits of Heterotrimeric G Proteins

“…With regard to fluid shear stress, these responses can be physiological or pathological depending on the type, magnitude, and direction of flow. Identification of the primary mechanosensor that enables vascular endothelial cells (ECs) 2 to discriminate between different flow profiles has been a major challenge in the field, although a number of candidate molecules, putative macromolecular complexes, and/or cell structures have been proposed (1,2).…”