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      Decreased Intercellular Communication and Connexin Expression in Mouse Aortic Endothelium during Lipopolysaccharide-Induced Inflammation

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          Abstract

          The role of gap junctional intercellular communication during inflammatory processes is not well understood. In particular, changes in the expression and function of vascular endothelial connexins (gap junction proteins) in response to inflammatory agents has not been fully investigated. In this study, we used intercellular dye transfer methods to assess interendothelial communication in aortic segments isolated from mice treated with or without intraperitoneal lipopolysaccharide (LPS), a potent inflammatory mediator. LPS treatment resulted in a 49% decrease in endothelial dye coupling 18 h after injection. Western blots indicated that LPS treatment also caused a reduction in endothelial connexin40 (Cx40) levels to 33% of control levels. Connexin37 (Cx37) levels decreased only slightly after LPS treatment to 79% of control levels. We also examined endothelial communication in aortic segments isolated from Cx37<sup>–/–</sup> and Cx40<sup>–/–</sup> mice. LPS treatment caused a significantly greater decrease in dye transfer in endothelium isolated from Cx37<sup>–/–</sup> animals compared with endothelium from Cx40<sup>–/–</sup> animals (71 vs. 26% decrease). LPS injection caused a reduction in Cx40 levels in Cx37<sup>–/–</sup> endothelium, whereas LPS actually increased Cx37 levels in Cx40<sup>–/–</sup> endothelium. These results suggest that LPS mediates changes in endothelial gap junction-mediated communication, at least in part, through modulation of Cx40 and Cx37 levels.

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          Most cited references 37

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          Structural and functional diversity of connexin genes in the mouse and human genome.

          Gap junctions are clustered channels between contacting cells through which direct intercellular communication via diffusion of ions and metabolites can occur. Two hemichannels, each built up of six connexin protein subunits in the plasma membrane of adjacent cells, can dock to each other to form conduits between cells. We have recently screened mouse and human genomic data bases and have found 19 connexin (Cx) genes in the mouse genome and 20 connexin genes in the human genome. One mouse connexin gene and two human connexin genes do not appear to have orthologs in the other genome. With three exceptions, the characterized connexin genes comprise two exons whereby the complete reading frame is located on the second exon. Targeted ablation of eleven mouse connexin genes revealed basic insights into the functional diversity of the connexin gene family. In addition, the phenotypes of human genetic disorders caused by mutated connexin genes further complement our understanding of connexin functions in the human organism. In this review we compare currently identified connexin genes in both the mouse and human genome and discuss the functions of gap junctions deduced from targeted mouse mutants and human genetic disorders.
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            Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster.

            Recognition of bacterial lipopolysaccharide (LPS) by the innate immune system elicits strong pro-inflammatory responses that can eventually cause a fatal sepsis syndrome in humans. LPS-mediated activation of mammalian cells is believed to involve the interaction of LPS with lipopolysaccharide-binding protein (LBP) in the serum and, subsequently with CD14. Although there is no doubt that CD14 binds LPS, CD14 is not capable of initiating a transmembrane activation signal because it is a glycosylphosphatidylinositol (GPI)-anchored protein. Accumulating evidence has suggested that LPS must interact with a transmembrane receptor(s) that is responsible for signal transduction. Integrins CD11c and/or CD18, Toll-like receptors (TLRs), as well as CD55, have been suggested to serve this function. Recently, we have revealed that a signalling complex of receptors is formed following LPS stimulation, which comprises heat-shock proteins (Hsps) 70 and 90, chemokine receptor 4 (CXCR4) and growth differentiation factor 5 (GDF5). Taking into account the discovery of the TLRs and the LPS-activation cluster, we propose a new model of LPS recognition.
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              Female infertility in mice lacking connexin 37.

              The signals regulating ovarian follicle development and the mechanisms by which they are communicated are largely undefined. At birth, the ovary contains primordial follicles consisting of meiotically arrested oocytes surrounded by a single layer of supporting (granulosa) cells. Periodically, subsets of primordial follicles undergo further development during which the oocyte increases in size and the granulosa cells proliferate, stratify and develop a fluid-filled antrum. After ovulation, oocytes resume meiosis and granulosa cells retained in the follicle differentiate into steroidogenic cells, forming the corpus luteum. It has been proposed that intercellular signalling through gap junction channels may influence aspects of follicular development. Gap junctions are aggregations of intercellular channels composed of connexins, a family of at least 13 related proteins that directly connect adjacent cells allowing the diffusional movement of ions, metabolites, and other potential signalling molecules. Here we show that connexin 37 is present in gap junctions between oocyte and granulosa cells and that connexin 37-deficient mice lack mature (Graafian) follicles, fail to ovulate and develop numerous inappropriate corpora lutea. In addition, oocyte development arrests before meiotic competence is achieved. Thus, cell-cell signalling through intercellular channels critically regulates the highly coordinated set of cellular interactions required for successful oogenesis and ovulation.
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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
                2004
                August 2004
                30 September 2004
                : 41
                : 4
                : 323-333
                Affiliations
                aDepartment of Physiology, University of Arizona, Tucson, Ariz., and bDepartment of Pediatrics, Mayo Clinic College of Medicine, Rochester, Minn., USA
                Article
                79614 J Vasc Res 2004;41:323–333
                10.1159/000079614
                15249738
                © 2004 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: 5, Tables: 2, References: 61, Pages: 11
                Categories
                Research Paper

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