Shear Stress Increases ICAM-1 and Decreases VCAM-1 and E-selectin Expressions Induced by Tumor Necrosis Factor-α in Endothelial Cells

Abstract

Objective-Vascular endothelial cells (ECs) are subjected to shear stress and cytokine stimulation. We studied the interplay between shear stress and cytokine in modulating the expression of adhesion molecule genes in ECs. Methods and Results-Shear stress (20 dynes/cm2 ) was applied to ECs prior to and/or following the addition of tumor necrosis factor (TNF)-␣. Shear stress increased the TNF-␣-induced expression of intercellular adhesion molecule-1 (ICAM-1) at both mRNA and surface protein levels, but decreased the TNF-␣-induced expression of vascular adhesion molecule-1 (VCAM-1) and E-selectin. Transfection studies using promoter reporter gene constructs of ICAM-1, VCAM-1, and E-selectin demonstrated that these shear stress modulations of gene expression occur at the transcriptional levels. After 24-hour preshearing followed by 1 hour of static incubation, the effect of preshearing on TNF-␣-induced ICAM-1 mRNA expression vanished. The recovery of the TNF-␣-induced VCAM-1 and E-selectin mRNA expressions following preshearing, however, required a static incubation time of Ͼ6 hours (complete recovery at 24 hours). Pre-and postshearing caused a reduction in the nuclear factor-B-DNA binding activity induced by TNF-␣ in the EC nucleus. V ascular endothelial cells (ECs) are constantly exposed to fluid shear stress, a tangential force generated by the velocity gradient in viscous fluid flow. The nature and magnitude of shear stress play a significant role in the homeostasis of the structure and function of the blood vessel. Recent evidence suggests that physiological levels of laminar shear stress modulate cellular signaling and EC function and are protective against atherogenesis. 1 In human carotid and coronary arteries, atherosclerotic plaques are found in the vicinity of arterial bifurcations and bends, where the local flow is disturbed. 2 In contrast, regions of artery that experience laminar non-oscillatory shear stress were protected from atherosclerosis. The cytokine tumor necrosis factor-␣ (TNF-␣) is an important mediator of the inflammatory processes that occur during the progression of atherosclerosis. 3 Produced by macrophages that infiltrate the lesion, cytokines such as TNF-␣ are known to induce the expression of many endothelial genes that contribute to the complex processes involved in atherogenesis. 3 Well know examples include the transcriptional regulation of various adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. 3 In contrast to laminar shear stress, cytokines are generally considered to be proatherogenic factors. Conclusions-OurDespite the intensive studies on the effects of fluid shear stress on ECs, the interplay of shear stress and cytokines in modulating EC gene expression and function has not fully been clarified. It has been shown that physiological levels of laminar shear stress inhibit the apoptosis of ECs induced by TNF-␣ and H 2 O 2 . 4,5 This inhibitory effect of shear stress is mediated by signalin...

Characterization of Umbilical Cord Blood–Derived Late Outgrowth Endothelial Progenitor Cells Exposed to Laminar Shear Stress

“…CB-EPCs on FN under static conditions and exposed to TNF-a did have a significantly higher amount of E-selectin compared to all other conditions; however, this protein expression was significantly downregulated under flow conditions. The effect of flow on adhesion molecule protein levels after TNF-a stimulation was similar to that reported by Chiu et al 54 Overall, these results suggest that CB-EPCs are similar when compared to HAECs' protein expression of important monocyte adhesion molecules, and prevent monocyte adhesion in vitro.…”

Map Kinase Phosphatase-1 Suppresses Endothelial Activation in Regions of the Arterial Tree That Are Resistant to Atherosclerosis

“…These data suggest that the protective effects of high shear stress persist for several hours when vessels are exposed to static conditions, a concept that is consistent with previous studies of the responses of cultured EC to shear 27 . In contrast, parallel studies of aortae from MKP-1 -/-mice demonstrated that EC in an atheroprotected region were sensitive to LPS treatment which activated p38 and JNK and induced high levels of VCAM-1.…”

“…Finally, prolonged high shear exerts several protective effects on cultured EC including inhibition of the cell cycle 24 , promotion of viability 20 and suppression of pro-inflammatory activation 22,[25][26][27] .…”

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

“…The mechanism may involve eNOS, which was induced by ivabradine in our study and is known to inhibit inflammation via NO-dependent nitrosylation of pro-inflammatory signalling intermediaries and transcription factors 21,37 . Notably, previous studies revealed that high WSS enhanced the expression of eNOS and reduced VCAM-1 [18][19][20][21] . Thus we hypothesize that ivabradine suppresses EC expression of VCAM-1 via WSS-dependent induction of eNOS.…”

“…Low WSS promotes atherosclerosis by inducing endothelial expression of inflammatory molecules (e.g. VCAM-1) that promote lesions [18][19][20] , whereas high unidirectional WSS induces anti-inflammatory genes such as eNOS 21 . Although ivabradine is known to increase stroke volume and coronary perfusion 22 , its effects on WSS have not been studied.…”