Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

Abstract

DeVerse JS, Sandhu AS, Mendoza N, Edwards CM, Sun C, Simon SI, Passerini AG. Shear stress modulates VCAM-1 expression in response to TNF-␣ and dietary lipids via interferon regulatory factor-1 in cultured endothelium. Am J Physiol Heart Circ Physiol 305: H1149-H1157, 2013. First published August 9, 2013; doi:10.1152/ajpheart.00311.2013.-Dyslipidemia is a primary risk factor for cardiovascular disease, but the specific mechanisms that determine the localization of atherosclerotic plaques in arteries are not well defined. Triglyceride-rich lipoproteins (TGRL) isolated from human plasma after a high-fat meal modulate TNF-␣-induced VCAM-1 expression in cultured human aortic endothelial cells (HAECs) via an interferon regulatory factor (IRF)-1-dependent transcriptional mechanism. We examined whether fluid shear stress acts as a mediator of IRF-1-dependent VCAM-1 expression in response to cytokine and dietary lipids. IRF-1 and VCAM-1 were examined by immunofluorescence in TNF-␣-stimulated HAEC monolayers exposed to TGRL and a linear gradient of shear stress ranging from 0 to 16 dyn/cm 2 in a microfluidic device. Shear stress alone modulated TNF-␣-induced VCAM-1 expression, eliciting a 150% increase at low shear stress (2 dyn/cm 2 ) and a 70% decrease at high shear stress (12 dyn/cm 2 ) relative to static. These differences correlated with a 60% increase in IRF-1 expression under low shear stress and a 40% decrease under high shear stress. The addition of TGRL along with cytokine activated a fourfold increase in VCAM-1 expression and a twofold increase in IRF-1 expression. The combined effect of shear stress and TGRL on the upregulation of membrane VCAM-1 was abolished by transfection of HAECs with IRF-1-specific small interfering RNA. In a healthy swine model, elevated levels of endothelial IRF-1 were also observed within atherosusceptible regions of the aorta by Western blot analysis and immunohistochemistry, implicating arterial hemodynamics in the regulation of IRF-1 expression. These data demonstrate direct roles for fluid shear stress and postprandial TGRL from human serum in the regulation of IRF-1 expression and downstream inflammatory responses in HAECs.atherosclerosis; hemodynamics; hypertriglyceridemia; endothelial dysfunction; inflammation; vascular cell adhesion molecule 1; tumor necrosis factor-␣ ATHEROSCLEROSIS is a multifactorial disease characterized by the focal accumulation of lipid-rich plaques at arterial sites that correlate strongly with regions of disturbed blood flow. Diets high in saturated and nonesterified fats contribute to a state of metabolic dysregulation that is associated with chronic lowgrade inflammation and activation of stress responses that accelerate the progression of atherosclerosis (18,21). Elevated levels of circulating lipoproteins and cytokines, such as TNF-␣, contribute to inflammatory responses that culminate in the preferential recruitment of leukocytes to the endothelium via the upregulation of cell adhesion molecules, including VCAM-1 (24). Despite the recognition that...

Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFκB

“…Similar findings were observed by Dagia et al [30] who found that TNF-α activation of endothelial cells results in IRF-1-mediated VCAM-1 expression through binding of IRF-1 to the VCAM-1 promotor. Similarly, DeVerse et al [31] showed that in cultured endothelial cells, fluid shear stress signaling, synergistic with postprandial triglyceride-rich lipoproteins, transcriptionally augments cytokine-induced VCAM-1 expression in an IRF-1-dependent manner. In addition, Warfel and Agnillo [32] reported that anthrax lethal toxin enhanced nuclear expression of endothelial IRF-1 and induced VCAM-1 expression.…”

“…Both this latter study and our study were performed under static conditions. Previous studies found monocyte adhesion to TNF-α-treated endothelium to be regulated by IRF-1-mediated VCAM-1 induction under flow conditions [20,30,31] . In patients with septic shock, increased endothelial permeability and vasodilation result in a dramatic drop in blood flow rate in certain microvascular compartments such as the capillaries [6,7,9] .…”

Impact of prolonged sitting on lower and upper limb micro‐ and macrovascular dilator function

“…Shear stress not only stimulates endothelium-dependent dilation but is also a required signal for sustaining an anti-atherogenic vascular cell phenotype. Indeed, the role of shear stress in maintaining vascular health is supported by endothelial cell culture models (Mohan et al , 2003a; Mohan et al , 2003b; DeVerse et al , 2013; Ishibazawa et al , 2013), studies in perfused isolated arteries (Yamawaki et al , 2003; Woodman et al , 2005; Gambillara et al , 2006; Padilla et al , 2014), in vivo animal experiments (Korshunov & Berk, 2003; Nam et al , 2009; Wang et al , 2011; Loyer et al , 2014), and studies in human subjects (Thijssen et al , 2009; Tinken et al , 2009; Ishibazawa et al , 2013; Jenkins et al , 2013; Johnson et al , 2013). For example, Woodman et al .…”

Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats

“…Hydrodynamic experiments were performed on HAEC monolayers using a microfluidic flow chamber device based on Hele-Shaw stagnation flow theory (14,46). The device induces a linearly decreasing WSS profile along the center line of the longitudinal axis for a given flow rate when vacuum adhered to a cell monolayer, facilitating the study of a wide range in WSS magnitudes within a single cell monolayer, while preserving information related to the spatial heterogeneity of response.…”