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      Continuous Endothelial Cell Activation Increases Angiogenesis: Evidence for the Direct Role of Endothelium Linking Angiogenesis and Inflammation

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          Abstract

          There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor-α (TNF-α), we have established models of stable TNF-α expression in endothelial cells in vitro and in transgenic mice in vivo. In the in vitro model, continuous endothelial activation leads to increased leukocyte cellular adhesion molecule expression and intracellular reactive oxygen species, hallmarks of a proinflammatory and dysfunctional endothelium. In addition, stable expression of TNF-α in endothelial cells increased angiogenic sprout formation in the presence but also in the absence of angiogenic growth factors. The partial neutralization of this effect by TNF-α antibodies and the inability of conditioned media from stable TNF-α-expressing endothelial cells to induce angiogenic activities in control endothelial cells suggest that this effect does not require expression of additional autocrine factors, but is an autonomous effect of the transmembrane TNF on the endothelial cells. Furthermore, using the Matrigel plug assay in vivo, increased angiogenesis was observed in endothelial TNF-α-expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF-α can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.

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          Most cited references 27

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          Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.

          Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.
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            Chemistry and biology of vitamin E.

            Our understanding of the role of vitamin E in human nutrition, health, and disease has broadened and changed over the past two decades. Viewed initially as nature's most potent lipid-soluble antioxidant (and discovered for its crucial role in mammalian reproduction) we have now come to realize that vitamin E action has many more facets, depending on the physiological context. Although mainly acting as an antioxidant, vitamin E can also be a pro-oxidant; it can even have nonantioxidant functions: as a signaling molecule, as a regulator of gene expression, and, possibly, in the prevention of cancer and atherosclerosis. Since the term vitamin E encompasses a group of eight structurally related tocopherols and tocotrienols, individual isomers have different propensities with respect to these novel, nontraditional roles. The particular beneficial effects of the individual isomers have to be considered when dissecting the physiological impact of dietary vitamin E or supplements (mainly containing only the alpha-tocopherol isomer) in clinical trials. These considerations are also relevant for the design of transgenic crop plants with the goal of enhancing vitamin E content because an engineered biosynthetic pathway may be biased toward formation of one isomer. In contrast to the tremendous recent advances in knowledge of vitamin E chemistry and biology, there is little hard evidence from clinical and epidemiologic studies on the beneficial effects of supplementation with vitamin E beyond the essential requirement.
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              Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species.

              In this study we examined the effect of oxidized low density lipoprotein (ox-LDL) on the intracellular production of reactive oxygen species (ROS) in bovine aortic endothelial cells (BAECs) and whether this increase occurs through its binding to the endothelial receptor lectin-like ox-LDL receptor-1 (LOX-1). Furthermore, this study also aimed to ascertain whether the binding of ox-LDL to LOX-1 is associated with NF-kappaB activation. ox-LDL induced a significant dose-dependent increase in ROS production after a 30-s incubation with BAECs (p < 0.01). ROS formation was markedly reduced in BAECs incubated with anti-LOX-1 monoclonal antibody (p < 0.001), while control nonimmune IgG produced no effect. ox-LDL induced a time- and dose-dependent significant increase in ROS formation only in CHO-K1 cells stably expressing bovine LOX-1 (p < 0.001), while no increase was present in CHO-K1 cells. The activation of the transcription factor NF-kappaB in BAECs was evident after a 5-min incubation with ox-LDL and was attenuated by anti-LOX-1 monoclonal antibody. The conclusion is that one of the pathophysiological consequences of ox-LDL binding to LOX-1 may be the activation of NF-kappaB through an increased ROS production.
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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
                February 2006
                16 February 2006
                : 43
                : 2
                : 193-204
                Affiliations
                aDepartment of Cellular and Integrative Physiology, and bIndiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, cRoudebush VA Medical Center, Indianapolis, Ind., dDartmouth-Hitchcock Medical Center, Lebanon, N.H., USA; eMax-Planck-Institute, Bad Nauheim, and fInstitut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
                Article
                90949 J Vasc Res 2006;43:193–204
                10.1159/000090949
                16410682
                f98bb99b-0115-478c-9f30-f81fa0baf5f1
                © 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: 5, References: 55, Pages: 12
                Categories
                Research Paper

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