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      Balance between Angiopoietin-1 and Angiopoietin-2 Is in Favor of Angiopoietin-2 in Atherosclerotic Plaques with High Microvessel Density

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          Abstract

          Introduction: Atherosclerotic plaque microvessels are associated with plaque hemorrhage and rupture. The mechanisms underlying plaque angiogenesis are largely unknown. Angiopoietin (Ang)-1 and -2 are ligands of the endothelial receptor Tie-2. Ang-1 induces formation of stable vessels, whereas Ang-2 destabilizes the interaction between endothelial cells and their support cells. We studied the expression patterns of Ang-1 and -2 in relation to plaque microvessels. Methods and Results: Carotid endarterectomy specimens were studied (n = 100). Microvessel density (MVD) was correlated with the presence of macrophages and with a (fibro)atheromatous plaque phenotype. A negative correlation was observed between Ang-1 expression and MVD. A positive correlation was observed between the ratio of Ang-2/Ang-1 and MVD. Ang-2 expression was correlated with matrix metalloproteinase-2 (MMP-2) activity. Immunohistochemical staining of Ang-1 was observed in smooth muscle cells, whereas Ang-2 was detected in endothelial cells, smooth muscle cells and macrophages. Conclusions: In plaques with high MVD, the local balance between Ang-1 and Ang-2 is in favor of Ang-2. Plaque Ang-2 levels are associated with MMP-2 activity. Ang-2-induced MMP-2 activity might play a role in the development of (unstable) plaque microvessels.

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          Most cited references 25

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          Vascular-specific growth factors and blood vessel formation.

          A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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            Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

            The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
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              Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1.

              Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and VEGF had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Ang1 therefore may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEGF and, in combination with VEGF, for promoting growth of nonleaky vessels.
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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
                2008
                April 2008
                10 January 2008
                : 45
                : 3
                : 244-250
                Affiliations
                aUniversity Medical Center and bInteruniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands
                Article
                112939 J Vasc Res 2008;45:244–250
                10.1159/000112939
                18182823
                © 2008 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, References: 33, Pages: 7
                Categories
                Research Paper

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