Disturbed Cyclical Stretch of Endothelial Cells Promotes Nuclear Expression of the Pro-Atherogenic Transcription Factor NF-κB

Abstract

Exposure of endothelial cells to low and multidirectional blood flow is known to promote a pro-atherogenic phenotype. The mechanics of the vessel wall is another important mechano-stimulus within the endothelial cell environment, but no study has examined whether changes in the magnitude and direction of cell stretch can be pro-atherogenic. Herein, we developed a custom cell stretching device to replicate the in vivo stretch environment of the endothelial cell and examined whether low and multidirectional stretch promote nuclear translocation of NF-κB. A fluid–structure interaction model of the device demonstrated a nearly uniform strain within the region of cell attachment and a negligible magnitude of shear stress due to cyclical stretching of the cells in media. Compared to normal cyclical stretch, a low magnitude of cyclical stretch or no stretch caused increased expression of nuclear NF-κB (p = 0.09 and p < 0.001, respectively). Multidirectional stretch also promoted significant nuclear NF-κB expression, comparable to the no stretch condition, which was statistically higher than the low (p < 0.001) and normal (p < 0.001) stretch conditions. This is the first study to show that stretch conditions analogous to atherogenic blood flow profiles can similarly promote a pro-atherogenic endothelial cell phenotype, which supports a role for disturbed vessel wall mechanics as a pathological cell stimulus in the development of advanced atherosclerotic plaques.

Low Shear Stress Upregulates CX3CR1 Expression by Inducing VCAM-1 via the NF-κB Pathway in Vascular Endothelial Cells

“…NF-κB and its regulatory genes are both directly and indirectly involved in the development of atherosclerosis. Ryan et al demonstrated that low shear stress can promote nuclear expression of NF-κB [21]. Therefore, we investigated if the NF-κB signaling pathway is involved in low shear stress-mediated upregulation of CX3CR1.…”

Disturbed flow induces a sustained, stochastic NF-κB activation which may support intracranial aneurysm growth in vivo

“…Shear stress is the drag force (per unit area) imposed on the endothelium by the blood flow which regulates all components of the NF-κB pathway 8 – 11 , but the nature of the velocity pattern that regulates the NF-κB pathway is still under debate 10 , 12 – 15 . According to older studies, stationary low shear stress [0.1–0.5 N/m or Pa] is sufficient to activate the pathway 12 , 13 , 15 , whereas other studies indicate that pulsatile shear stress 10 , 11 , 15 and/or disturbed shear stress 11 , 14 are essential for its activation.…”

Endothelial Cell Biomechanical Responses are Dependent on Both Fluid Shear Stress and Tensile Strain

“…8,20,33 Blood pressure exerted on the blood vessel wall can cause blood vessels to stretch. Physiological stretch has been reported to be athero-protective, 58 while excessive stretch can increase EC permeability 5 and superoxide production, 83 causing inflammation.…”