p47phox-Dependent NADPH Oxidase Regulates Flow-Induced Vascular Remodeling

Castier, Yves; Brandes, Ralf P.; Lesèche, Guy; Tedgui, Alain; Lehoux, Stéphanie

doi:10.1161/01.res.0000181759.63239.21

Cited by 200 publications

(196 citation statements)

References 44 publications

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“…Using an arteriovenous fistula model in wild-type and knockout mice, flow-induced vascular remodeling has been shown to involve MMP activity that is mediated by the NADPH oxidases and nitric oxide-dependent mechanisms. 42 In a rabbit model using a carotid branch ligation method, low flow was shown to upregulate MMP-2 and MMP-9. 43 Shear stress regulates structure and function of endothelial cells and plays an important role in atherosclerosis development.…”

Section: Discussionmentioning

confidence: 99%

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Platt

Ankeny

2006

Vascular Pharmacology

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Objective-The cysteine proteases, cathepsins, have been implicated in vascular remodeling and atherosclerosis, processes known to be regulated by shear stress. It is not known, however, whether shear regulates cathepsins. We examined the hypothesis that shear stress regulates cathepsin activity in endothelial cells. Methods and Results-Mouse aortic endothelial cells (MAECs) exposed to atheroprotective, unidirectional laminar shear (LS) degraded significantly less BODIPY-labeled elastin and gelatin in comparison to static and proatherogenic oscillatory shear (OS). The cathepsin inhibitor E64 also reduced this activity. Gelatin zymography showed that cathepsin activity of MAECs was blunted by LS exposure and by a cathepsin L inhibitor but not by cathepsin B and S inhibitors, whereas a cathepsin K inhibitor had a minor effect. Cathepsin L siRNA knocked down cathepsin L expression, gelatinase, and elastase activity in OS and static MAECs. A partial reduction of cathepsin B protein raised the possibility that the siRNA effect on the matrix protease activity could have been attributable to cathepsin L or B. Cathepsin B activity study using the synthetic peptide showed it was not regulated by shear. Key Words: shear stress Ⅲ cathepsin Ⅲ elastase Ⅲ gelatinase Ⅲ atherosclerosis V ascular endothelial cells are constantly exposed to fluid shear stress, the frictional force generated by blood flow over the vascular endothelium. The importance of shear stress in vascular biology and pathophysiology has been highlighted by the focal development patterns of atherosclerosis in hemodynamically defined regions. For example, the regions of branched and curved arteries exposed to disturbed flow conditions including oscillatory and low mean shear stresses (OS) correspond to atheroprone areas. In contrast, straight arteries exposed to pulsatile high levels of laminar shear stress (LS) are relatively well protected from atherosclerotic plaque development. 1 Changes in blood flow have been shown to be a critical factor inducing arterial remodeling. 1-7 Increases in arterial wall shear stress prevent vascular remodeling leading to thickening of the vascular wall and inflammation, 2 whereas decreases in arterial wall shear stress promote arterial remodeling and inflammation. 2,3 Additionally, low wall shear stress leads to degradation of the internal elastic lamina (IEL). 5 Despite these findings, the underlying mechanisms by which shear regulates proteases degrading vessel wall matrix and IEL are not well described. Although there is a report demonstrating that shear regulates matrix metalloproteases (MMPs) in endothelial cells, 8 it is not clear whether other proteases are also regulated by shear. Conclusions-TheseCathepsins are the papain family of cysteine proteases which degrade elastin in addition to collagen. 9 Unlike MMPs, the role for cathepsins in blood vessel remodeling and cardiovascular disease has been understudied until recently. Cathepsins K, L, and S, potent elastinolytic proteases, have been identified in atheroscleroti...

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Section: Discussionmentioning

confidence: 99%

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Platt

Ankeny

2006

Vascular Pharmacology

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“…One explanation for this response is shear-mediated vasodilation. Vasodilation is a mechanism used in other biological states, including vessel blockage, to expand the lumen and restore shear stress to normal levels [51,52]. Studies in the chick embryo have shown that the zinc finger transcription factor Krü ppel-like factor 2 (KLF2) (induced by high shear stress and an activator of shear-mediated vasodilation [53]) is expressed in early embryonic endocardial cells of the OFT [54].…”

Section: Discussionmentioning

confidence: 99%

Blood flow through the embryonic heart outflow tract during cardiac looping in HH13–HH18 chicken embryos

Midgett

Chivukula

Dorn

et al. 2015

J. R. Soc. Interface.

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Blood flow is inherently linked to embryonic cardiac development, as haemodynamic forces exerted by flow stimulate mechanotransduction mechanisms that modulate cardiac growth and remodelling. This study evaluated blood flow in the embryonic heart outflow tract (OFT) during normal development at each stage between HH13 and HH18 in chicken embryos, in order to characterize changes in haemodynamic conditions during critical cardiac looping transformations. Two-dimensional optical coherence tomography was used to simultaneously acquire both structural and Doppler flow images, in order to extract blood flow velocity and structural information and estimate haemodynamic measures. From HH13 to HH18, peak blood flow rate increased by 2.4-fold and stroke volume increased by 2.1-fold. Wall shear rate (WSR) and lumen diameter data suggest that changes in blood flow during HH13-HH18 may induce a shear-mediated vasodilation response in the OFT. Embryo-specific four-dimensional computational fluid dynamics modelling at HH13 and HH18 complemented experimental observations and indicated heterogeneous WSR distributions over the OFT. Characterizing changes in haemodynamics during cardiac looping will help us better understand the way normal blood flow impacts proper cardiac development.

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“…Genetic deletion of either MMP-2 or MMP-9 reduces VSMC migration . In a flow-dependent model of injury created by an A-V fistula, Castier et al (2005) showed that MMP-9, but not MMP-2, is increased, resulting in outward remodeling. Since MMP-9 has been found to be elevated in acute coronary syndromes and because apoE/MMP-9 double knockout mice have larger atherosclerotic plaques, MMP-9 may be involved in the recruitment of VSMCs after plaque rupture (Johnson et al 2005).…”

Section: Vascular Smooth Muscle Cell Migrationmentioning

confidence: 99%

“…The novel Nox inhibitor VAS2870 attenuates PDGF-induced migration (Ten Freyhaus et al 2006). Furthermore, in vivo studies have shown that remodeling is delayed in p47phox−/− mice and is completely abolished in mice lacking eNOS, suggesting that early remodeling requires NADPH oxidasederived ROS, while late remodeling is more dependent on ONOO • generated by eNOS (Castier et al 2005). …”

Section: Vascular Smooth Muscle Cell Migrationmentioning

confidence: 99%

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

Papaharalambus

Griendling

2007

Trends in Cardiovascular Medicine

285

220

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The development of vascular disease has its origins in an initial insult to the vessel wall by biological or mechanical factors. The disruption of homeostatic mechanisms leads to alteration of the original architecture of the vessel and its biological responsiveness, contributing to acute or chronic diseases such as stroke, hypertension and atherosclerosis. Endothelial dysfunction, macrophage infiltration of the vessel wall, and proliferation and migration of smooth muscle cells all involve different types of reactive oxygen species, produced by various vessel wall components. Although basic science and animal research have clearly established the role of reactive oxygen species in the progression of vascular disease, the failure of clinical trials with antioxidant compounds has underscored the need for better antioxidant therapies and a more thorough understanding of the role of reactive oxygen species in cardiovascular physiology and pathology.The fundamental processes underlying the development of vascular diseases such as atherosclerosis, restenosis and hypertensive vascular remodeling have their origins in an initial insult to the vessel wall. Such an insult may arise from mechanical disruption that occurs during percutaneous coronary angioplasty or at regions of oscillatory shear stress, or it can result from biological causes, such as hypercholesterolemia, excess free radicals, diabetes, increased concentrations of plasma homocysteine, or infectious agents. Injury promotes disruption of the homeostatic mechanisms of the endothelial protective barrier, changing its natural properties, increasing its adhesiveness to leukocytes and altering its permeability. This endothelial dysfunction also leads to the formation of vasoactive molecules, which in turn induce inflammatory genes, inactivate nitric oxide (NO • ) and its protective functions, and activate matrix metalloproteinases, leading to extracellular matrix remodeling, and increased smooth muscle cell (VSMC) growth, migration and proliferation. Each of these processes contributes to thickening of the vessel wall or the formation of lesions that can lead to hypertension, acute myocardial infarction and stroke. Reactive Oxygen Species and Vascular InjuryIn the past decade a staggering amount of evidence implicates a common denominator, reactive oxygen species (ROS), in the development of most cardiovascular diseases (Figure 1). Superoxide (O 2 •− ) and hydrogen peroxide (H 2 O 2 ) are two of the most biologically important ROS in the cardiovascular system, and are produced in vascular cells by a number of oxidases, including the NADPH oxidases (Nox) and xanthine oxidase, lipoxygenases, cytochrome p450,

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p47phox-Dependent NADPH Oxidase Regulates Flow-Induced Vascular Remodeling

Cited by 200 publications

References 44 publications

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Blood flow through the embryonic heart outflow tract during cardiac looping in HH13–HH18 chicken embryos

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

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