Differential activation of NF-kappa B in human aortic endothelial cells conditioned to specific flow environments

Mohan, Sumathy; Natarajan, Mohan; Sprague, Eugene A.

doi:10.1152/ajpcell.1997.273.2.c572

Cited by 152 publications

(108 citation statements)

References 18 publications

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“…We and others have shown, however, that exposure of EC to prolonged steady low shear (2 dyne/cm 2 ) induces sustained increases in endothelin-1 (a mitogen for vascular smooth muscle cells) release, as well as NFB, MCP-1, and VCAM-1 expression. 20,34,35 These observations suggest that steady low shear may be another biomechanical risk factor. Taken together, the coordinated induction of these atherogenic factors may occur at the lesionprone area, where the disturbed hemodynamic flow patterns-low mean shear levels associated with temporal gradients in shear-prevail, and thus may be one of the mechanisms contributing to the focal distribution of early atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 95%

“…17 Exposure of EC to fluid shear also stimulates the activation of transcription factors, such as egr-1, 18 AP-1, 19 and NFB. 19,20 Activated egr-1 binds to the proximal PDGF-A promoter by displacing sp-1 from their overlapping recognition element, and the egr-1 binding site has been identified as a cis-element for the induction of PDGF-A by fluid shear. 18 The promoter of MCP-1 gene contains both NFB and AP-1 binding sites, which may coordinately modulate shear inducibility of MCP-1.…”

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confidence: 99%

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Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells

Bao

Frangos

1999

ATVB

201

121

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Abstract-Three well-defined laminar flow profiles were created to distinguish the influence of a gradient in shear and steady shear on platelet-derived growth factor A (PDGF-A) and monocyte chemoattractant protein-1 (MCP-1) expression in human endothelial cells. The flow profiles (16 dyne/cm 2 maximum shear stress) were ramp flow (shear stress smoothly transited at flow onset), step flow (shear stress abruptly applied at flow onset), and impulse flow (shear stress abruptly applied for 3 s only). Ramp flow induced only minor expression of PDGF-A and did not increase MCP-1 expression.Step flow increased PDGF-A and MCP-1 mRNA levels 3-and 2-fold at 1.5 hours, respectively, relative to ramp flow. In contrast, impulse flow increased PDGF-A and MCP-1 expression 6-and 7-fold at 1.5 hours, and these high levels were sustained for at least 4 hours. These results indicate that a temporal gradient in shear (impulse flow and the onset of step flow) and steady shear (ramp flow and the steady component of step flow) stimulates and diminishes the expression of PDGF-A and MCP-1, respectively. NO synthase inhibitor N G -amino-L-arginine (L-NAA) was found to markedly enhance MCP-1 and PDGF-A expression induced by step flow, but decrease their expression induced by impulse flow, in a dose-dependent manner. NO donor spermine-NONOate (SPR/NO) dose-dependently reduced the MCP-1 and PDGF-A expression induced by impulse flow. Moreover, impulse flow was found to stimulate sustained (4 hours) IB-␣ degradation and egr-1 mRNA induction. L-NAA prevented IB-␣ degradation, whereas SPR/NO increased IB-␣ resynthesis 2 hours after impulse flow. The exact nature and influence of local shear involved in endothelial dysfunction leading to susceptibility for atherogenesis, however, remains unclear. Endothelial cells (EC) throughout the vasculature experience a variety of flow environments both with spatial variances and with temporal gradients in wall shear stress. In the venous system wall shear stress is lower and minimal gradients in shear stress exist because of the nonpulsatile nature of the blood flow. In the arterial system the flow conditions are generally assumed to be laminar and to present the endothelium with a high mean wall shear stress in addition to large temporal gradients in shear stress. At arterial bifurcations and curvatures, locations known to be highly prone to atherogenesis, disturbed flow patterns may develop that result in low mean wall shear stress, but still present the EC with large temporal gradients in shear stress. 3 These observations, combined with other in vitro evidence, 4 -6 suggest that gradients in shear and steady shear represent different biomechanical stimuli that differentially regulate local endothelial function by distinct signaling pathway, and thus contribute to the characteristic distribution pattern of atherosclerosis.A host of endothelial genes exhibit differential responses to shear stress stimuli that may be involved in the focal localization of atherogenic plaques. 7 The application of step shear...

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells

Bao

Frangos

1999

ATVB

201

121

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“…The transcription factors Klf2 and Klf4 are major mediators of the atheroprotective phenotype in high laminar flow (29,30), whereas NF-κB is a major proinflammatory transcription factor that promotes atherosclerosis (33). In vitro, onset of high-laminar FSS applied to ECs transiently activates the inflammatory transcription factor NF-κB; however, over several hours, cells align in the direction of flow and NF-κB declines to levels below baseline (34). Cell alignment in the direction of flow has therefore been proposed to be an adaptive mechanism that alters the way forces act on the cells (35).…”

Section: Discussionmentioning

confidence: 99%

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Baeyens

Mulligan-Kehoe

Corti

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

134

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Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4 −/− ) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4 −/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis. mechanotransduction | polarity | shear stress | atherosclerosis S yndecan 4 (S4) is a transmembrane heparan sulfate proteoglycan that serves as a coreceptor for extracellular matrix proteins and growth factors (1-3). S4−/− mice are viable and fertile (4, 5) but show defective wound healing consequent to impaired angiogenesis (6). They also have higher mortality after LPS injection (7) and exhibit defective muscle repair and myofiber organization as a result of inefficient differentiation and migration of muscle satellite cells (8). We and others have also demonstrated that S4 plays a critical role in the control of cell polarity, by controlling Rho GTPase activity (9-11), as well as in planar cell polarity (12). S4 has also been recently identified as a putative mechanosensor (13).Atherosclerosis is an inflammatory disease of large to midsized arteries that is the major cause of illness and death in developed nations and is rapidly increasing in developing nations (14,15). It is linked to a variety of risk factors including high LDL cholesterol level and triglycerides, diabetes, smoking, hypertension, sedentary lifestyle, and inflammatory mediators. However, atherosclerotic lesions occur selectively in regions of arteries that are subject to disturbances in fluid shear stress (FSS), the frictional force flowing blood exerts on the endothelium. Regions of arteries with lower flow magnitude, flow reversal, and other complex spatial/ temporal flow patterns are predisposed to atherosclerosis. Systemic risk factors appear to synergize with local biomechanical factors in the initiation and progression of atherosclerotic lesions (16).The importance of S4 in endothelial bi...

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“…There is a close relation between wall sheer stress, endothelial dysfunction, and the downstream inflammatory reaction (Nixon et al, 2010). In fact, the activity of the inflammatory transcription factor NF-kB is intimately modulated by the magnitude of shear stress exerted on vessel walls (Mohan et al, 1997). Hemodynamic stress was also found to alter the expression of several other genes that contribute to IA formation including MMP and TIMP (tissue inhibitors of MMPs) in a spatially localized manner within the aneurysm wall (Kadirvel et al, 2007).…”

Section: The Common Pathwaymentioning

confidence: 99%

Biology of Intracranial Aneurysms: Role of Inflammation

Chalouhi

Ali

Jabbour

et al. 2012

J Cereb Blood Flow Metab

440

418

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Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

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Differential activation of NF-kappa B in human aortic endothelial cells conditioned to specific flow environments

Cited by 152 publications

References 18 publications

Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells

Temporal Gradient in Shear But Not Steady Shear Stress Induces PDGF-A and MCP-1 Expression in Endothelial Cells

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Biology of Intracranial Aneurysms: Role of Inflammation

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