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J. Exp. Med. 205 (13): 3159-3171

Copyright © 2008 by the Rockefeller University Press.


ARTICLE

MyD88-dependent, superoxide-initiated inflammation is necessary for flow-mediated inward remodeling of conduit arteries

Paul C.Y. Tang1, Lingfeng Qin1, Jacek Zielonka6, Jing Zhou1, Catherine Matte-Martone2, Sonia Bergaya3, Nico van Rooijen7, Warren D. Shlomchik2, Wang Min4, William C. Sessa3, Jordan S. Pober5, , and George Tellides1

1 Departments of Surgery, 2 Medical Oncology, 3 Pharmacology, 4 Pathology, and 5 Immunobiology, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06510
6 Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226
7 Department of Molecular Cell Biology, Vrije Universiteit Medical Center, 1081 HV Amsterdam, Netherlands

CORRESPONDENCE George Tellides: george.tellides{at}yale.edu

Abstract: Vascular remodeling normalizes abnormal hemodynamic stresses through structural changes affecting vessel size and wall thickness. We investigated the role of inflammation in flow-mediated vascular remodeling using a murine model of partial outflow reduction without flow cessation or neointima formation. Common carotid arteries decreased in size after ipsilateral external carotid artery ligation in wild-type mice, but not in myeloid differentiation protein-88 (MyD88)–deficient mice. Inward remodeling was associated with MyD88-dependent and superoxide-initiated cytokine and chemokine production, as well as transient adventitial macrophage accumulation and activation. Macrophage depletion prevented flow-mediated inward vascular remodeling. Expression of MyD88 by intrinsic vascular cells was necessary for cytokine and chemokine production and changes in vessel size, whereas MyD88 expression by bone marrow–derived cells was obligatory for changes in vessel size. We conclude that there are at least two distinct roles for MyD88 in flow-mediated inward remodeling of conduit arteries. Our findings suggest that inflammation is necessary for vascular adaptation to changes in hemodynamic forces.


Abbreviations used: {alpha}-SMA, {alpha}-smooth muscle actin; Cav, caveolin; DHE, dihydroethidium; EC, endothelial cell; EEL, external elastic lamina; ICE, IL-1β converting enzyme; IP-10, IFN-{gamma}–induced protein of 10 kD; Mig, monokine induced by {gamma}-IFN; MyD88, myeloid differentiation protein-88; NOS, nitric oxide synthase; q, quantitative; ROS, reactive oxygen species; SMC, smooth muscle cell; SOD, superoxide dismutase; TLR, Toll-like receptor; TRIF, TIR domain-containing adapter inducing IFN-β; TXN, thioredoxin; VCAM, vascular cell adhesion molecule.

© 2008 Tang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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