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      Endothelium-Independent Flow-Induced Dilation in the Mouse Carotid Artery

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          Abstract

          Background: We investigated the locus of flow regulation of vascular tone in carotid arteries of C57 Bl/6 and eNOS<sup>–/–</sup> mice. Methods: Arterial segments (2–3 mm) were mounted in a perfusion myograph and preconstricted with 1 µ M phenylephrine before monitoring flow-induced changes in lumen diameter. Results: Both control and eNOS<sup>–/–</sup> mice demonstrated flow-dependent relaxation. This response was not attenuated by the NO synthase antagonist L-NAME, the cyclooxygenase inhibitor indomethacin, the selective guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), the adenylate cyclase inhibitor Rp-8-Br-cAMPs, integrin-binding RGD peptides, or by removal of the endothelium. Hypoxia, a physiological stimulus known to alter endothelium-dependent flow regulation of vascular tone, also failed to attenuate the observed flow-mediated dilation. Conclusions: These findings indicate the existence of a previously unidentified endothelium-independent mechanism of flow-induced dilation in the carotid artery. Further investigations to identify the mechanisms that underlie this response may provide novel therapeutic directions in the treatment of disorders characterized by abnormal flow regulation of vascular tone.

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          Most cited references 23

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          Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure

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            The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation.

            Atherosclerotic lesions form at distinct sites in the arterial tree, suggesting that hemodynamic forces influence the initiation of atherogenesis. If NF-kappaB plays a role in atherogenesis, then the activation of this signal transduction pathway in arterial endothelium should show topographic variation. The expression of NF-kappaB/IkappaB components and NF-kappaB activation was evaluated by specific antibody staining, en face confocal microscopy, and image analysis of endothelium in regions of mouse proximal aorta with high and low probability (HP and LP) for atherosclerotic lesion development. In control C57BL/6 mice, expression levels of p65, IkappaBalpha, and IkappaBbeta were 5- to 18-fold higher in the HP region, yet NF-kappaB was activated in a minority of endothelial cells. This suggested that NF-kappaB signal transduction was primed for activation in HP regions on encountering an activation stimulus. Lipopolysaccharide treatment or feeding low-density lipoprotein receptor knockout mice an atherogenic diet resulted in NF-kappaB activation and up-regulated expression of NF-kappaB-inducible genes predominantly in HP region endothelium. Preferential regional activation of endothelial NF-kappaB by systemic stimuli, including hypercholesterolemia, may contribute to the localization of atherosclerotic lesions at sites with high steady-state expression levels of NF-kappaB/IkappaB components.
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              Haemodynamic shear stress activates a K+ current in vascular endothelial cells.

              The endothelial lining of blood vessels is subjected to a wide range of haemodynamically-generated shear-stress forces throughout the vascular system. In vivo and in vitro, endothelial cells change their morphology and biochemistry in response to shear stress in a force- and time-dependent way, or when a critical threshold is exceeded. The initial stimulus-response coupling mechanisms have not been identified, however. Recently, Lansman et al. described stretch-activated ion channels in endothelial cells and suggested that they could be involved in the response to mechanical forces generated by blood flow. The channels were relatively nonselective and were opened by membrane stretching induced by suction. Here we report whole-cell patch-clamp recordings of single arterial endothelial cells exposed to controlled levels of laminar shear stress in capillary flow tubes. A K+ selective, shear-stress-activated ionic current (designated Ik.s) was identified which is unlike previously described stretch-activated currents. Ik.s varies in magnitude and duration as a function of shear stress (half-maximal effect at 0.70 dyn cm-2), desensitizes slowly and recovers rapidly and fully on cessation of flow. Ik.s activity represents the earliest and fastest stimulus-response coupling of haemodynamic forces to endothelial cells yet found. We suggest that localized flow-activated hyperpolarization of endothelium involving Ik.s may participate in the regulation of vascular tone.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2006
                July 2006
                28 July 2006
                : 43
                : 4
                : 383-391
                Affiliations
                aToronto General Hospital, bDivision of Respirology and Department of Critical Care, St. Michael’s Hospital, cHeart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Departments of dLaboratory Medicine and Pathobiology, ePhysiology and fObstetrics and Gynecology, Faculty of Medicine, University of Toronto and gSamuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Canada
                Article
                94414 J Vasc Res 2006;43:383–391
                10.1159/000094414
                16837773
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 1, References: 62, Pages: 9
                Categories
                Research Paper

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