Good advice for endothelial cells: Get in line, relax tension, and go with the flow

Abstract

Endothelial cells (ECs) are continuously subjected to fluid wall shear stress (WSS) and cyclic strain caused by pulsatile blood flow and pressure. It is well established that these hemodynamic forces each play important roles in vascular disease, but their combined effects are not well understood. ECs remodel in response to both WSS and cyclic strain to align along the vessel axis, but in areas prone to atherogenesis, such an alignment is absent. In this perspective, experimental and clinical findings will be reviewed, which have revealed the characteristics of WSS and cyclic strain, which are associated with atherosclerosis, spanning studies on whole blood vessels to individual cells to mechanosensing molecules. Examples are described regarding the use of computational modeling to elucidate the mechanisms by which EC alignment contributes to mechanical homeostasis. Finally, the need to move toward an integrated understanding of how hemodynamic forces influence EC mechanotransduction is presented, which holds the potential to move our currently fragmented understanding to a true appreciation of the role of mechanical stimuli in atherosclerosis.

FIG. 1.

Simple negative feedback loop. A disturbance u_d results in a deviation of a parameter u from the setpoint level u_t. A Comparator senses this deviation to result in a control signal u_c that is transduced into a compensatory action by the Effector to minimize the deviation.

FIG. 2.

Directional mechanical forces are anti-atherogenic, while non-directional forces are pro-atherogenic. (a) Directional forces (steady or pulsatile WSS with a significant forward component and circumferential cyclic strain) promote the alignment of the EC shape, actin stress fibers and traction forces aligned with the principal axis of the artery. (b) Non-directional forces (oscillatory/low WSS and cyclic equibiaxial strain) do not result in an alignment response. Non-directional forces induce an atherogenic EC phenotype characterized by inflammatory signaling, high cell turnover, and disrupted cell junctions, while directional forces have the opposite effect.

FIG. 3.

Negative feedback loop for cyclic stretch-induced cytoskeletal remodeling. Cyclic stretching of individual stress fibers results in a deviation of a fiber tension from the stall force of individual myosin II filaments. The myosin II filament compares the fiber tension with the stall force to respond by concentric (when the tension is below the stall force) or eccentric sliding (when the tension is above the stall force) to minimize the deviation in tension.

FIG. 4.

Effects of directional and non-directional WSS on EC shape. Pulsatile WSS (1.2 ± 0.6 Pa) for 12 h induces EC elongation in the direction of flow, effectively streamlining the cell shape. Oscillatory WSS (0 ± 0.6 Pa) does not change the cell shape relative to ECs in static culture.