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      Regulation of Postangiogenic Neovessel Survival by β 1 and β 3 Integrins in Collagen and Fibrin Matrices

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          Abstract

          We used the aortic ring model of angiogenesis to investigate the role of β<sub>1</sub> and β<sub>3</sub> integrins in postangiogenic vascular survival in collagen and fibrin matrices. Confocal microscopy studies showed that both β<sub>1</sub> and β<sub>3</sub> integrins were expressed in endothelial cells and pericytes of sprouting neovessels. Antibody blocking experiments demonstrated that β<sub>1</sub> integrins but not β<sub>3</sub> integrins were required for angiogenic sprouting in collagen. Conversely, in fibrin, blockade of both integrins was needed to inhibit angiogenesis whereas treatment with either antibody alone was ineffective. Antibody-mediated blockade of β<sub>1</sub> but not β<sub>3</sub> integrins accelerated vascular regression in collagen. In contrast, both anti-β<sub>1</sub> and -β<sub>3</sub> integrin antibodies were required to promote neovessel breakdown in fibrin. These results demonstrate that angiogenic sprouting and postangiogenic neovessel survival in collagen are critically dependent on β<sub>1</sub> integrins. They also indicate that these processes involve a redundant repertoire of β<sub>1</sub> and β<sub>3</sub> integrins when angiogenesis occurs in fibrin. Thus, pharmacologic targeting of integrin receptors aimed at blocking neovessel formation and survival must be tailored to the specific extracellular matrix environment in which angiogenesis takes place.

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          Most cited references 10

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          Fundamental concepts of the angiogenic process.

           Judah Folkman (2003)
          The process of angiogenesis encompasses the growth and regression of capillary blood vessels. Angiogenesis is finely regulated at the molecular and genetic levels, not unlike other physiologic processes such as coagulation, glucose metabolism, and blood pressure. During the development of the field of angiogenesis research over the past three decades, fundamental concepts have been introduced along the way in an attempt where possible, to unify new data from a variety of different laboratories. I have assembled here the major concepts which underlie the angiogenic process as we currently understand it. Many of these are now taken for granted, but this was not always the case, and I have tried to show how they were developed. My goal is to provide a conceptual framework for those basic scientists or clinicians who may enter this rapidly expanding field. Each concept discussed here is accompanied by a few key references as a guide to the pertinent literature.
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            A reevaluation of integrins as regulators of angiogenesis.

            Pharmacological agents directed against the integrins alpha(v)beta(3) and alpha(v)beta(5) have been reported to inhibit angiogenesis. However, genetic ablations of the genes encoding these integrins fail to block angiogenesis and in some cases even enhance it. This apparent paradox suggests the hypotheses that these integrins are negative regulators of angiogenesis and that the drugs targeting them may be acting as agonists rather than antagonists.
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              NF-κB Mediates αvβ3 Integrin-induced Endothelial Cell Survival

              The αvβ3 integrin plays a fundamental role during the angiogenesis process by inhibiting endothelial cell apoptosis. However, the mechanism of inhibition is unknown. In this report, we show that integrin-mediated cell survival involves regulation of nuclear factor-kappa B (NF-κB) activity. Different extracellular matrix molecules were able to protect rat aorta- derived endothelial cells from apoptosis induced by serum withdrawal. Osteopontin and β3 integrin ligation rapidly increased NF-κB activity as measured by gel shift and reporter activity. The p65 and p50 subunits were present in the shifted complex. In contrast, collagen type I (a β1-integrin ligand) did not induce NF-κB activity. The αvβ3 integrin was most important for osteopontin-mediated NF-κB induction and survival, since adding a neutralizing anti-β3 integrin antibody blocked NF-κB activity and induced endothelial cell death when cells were plated on osteopontin. NF-κB was required for osteopontin- and vitronectin-induced survival since inhibition of NF-κB activity with nonphosphorylatable IκB completely blocked the protective effect of osteopontin and vitronectin. In contrast, NF-κB was not required for fibronectin, laminin, and collagen type I–induced survival. Activation of NF-κB by osteopontin depended on the small GTP-binding protein Ras and the tyrosine kinase Src, since NF-κB reporter activity was inhibited by Ras and Src dominant-negative mutants. In contrast, inhibition of MEK and PI3-kinase did not affect osteopontin-induced NF-κB activation. These studies identify NF-κB as an important signaling molecule in αvβ3 integrin-mediated endothelial cell survival.
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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
                2007
                January 2007
                13 December 2006
                : 44
                : 1
                : 40-50
                Affiliations
                aDepartment of Pathology, University of Washington and bDivision of Pathology and Laboratory Medicine, Veterans Administration Puget Sound Health Care System, Seattle, Wash., USA; cLaboratory of Neurobiology and Neuroregenerative Medicine, Carlo Besta Institute, Milan, Italy
                Article
                97976 J Vasc Res 2007;44:40–50
                10.1159/000097976
                17167269
                © 2007 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: 7, References: 31, Pages: 11
                Categories
                Research Paper

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