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      Ultrastructural Changes in Endothelium during Apoptosis Indicate Low Microembolic Potential

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          Abstract

          Background: Apoptotic endothelium has been suggested to have microthrombotic and microembolic potential. While some describe pro-coagulant activities and platelet binding, others demonstrate maintained fibrinolytic protein and anti-platelet aggregatory activity. Canalicular fragmentation is unique to apoptotic endothelium and is suggested to facilitate size reduction of apoptotic cells to reduce microembolic potential. Despite the potential importance of apoptotic microemboli, there are no reports characterizing changes in cell size and shape during endothelial apoptosis. Methods: Here, we describe transmission and scanning electron microscopic studies of apoptotic endothelium and compare changes seen with apoptotic HL-60 cells incapable of canalicular fragmentation. Results: We demonstrate reduced endothelial size (p < 0.05) with progressive apoptosis relative to apoptotic HL-60 cells. Mechanical stress accelerated size reduction of apoptotic endothelium (p < 0.01) but did not affect the size of apoptotic HL-60 cells. Mechanical stress also increased circularity in apoptotic endothelium (p < 0.01), suggested to facilitate passage through small vessels. Earlier work indicated that canaliculi form through plasma membrane invagination, but we report fusion of small vesicles contributing to canalicular growth, while canaliculi fuse to form large vacuoles and also dilate at late stages of apoptosis. Conclusions: These observations are consistent with the suggestion that endothelium is adapted to minimize microembolic potential and that canalicular fragmentation contributes to this.

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          Most cited references 11

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          Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture

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            Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus.

            The restriction of phosphatidylserine (PtdSer) to the inner surface of the plasma membrane bilayer is lost early during apoptosis. Since PtdSer is a potent surface procoagulant, and since there is an increased incidence of coagulation events in patients with systemic lupus erythematosus (SLE) who have anti-phospholipid antibodies, we addressed whether apoptotic cells are procoagulant and whether anti-phospholipid antibodies influence this. Apoptotic HeLa cells, human endothelial cells, and a murine pre-B-cell line were markedly procoagulant in a modified Russell viper venom assay. This procoagulant effect was entirely abolished by addition of the PtdSer-binding protein, annexin V, confirming that it was PtdSer-dependent. The procoagulant effect was also abolished by addition of IgG purified from the plasma of three patients with anti-phospholipid antibody syndrome, but not IgG from normal controls. Confocal microscopy of apoptotic cells stained with fluorescein-isothiocyanate-conjugated-annexin V demonstrated (Ca2+)-dependent binding to the surface of membrane blebs o apoptotic cells, but not to intracellular membranes. Recent data indicate that the surface blebs of apoptotic cells constitute an important immunogenic particle in SLE. We propose that the PtdSer exposed on the outside of these blebs can induce the production of anti-phospholipid antibodies, which might also enhance the immunogenicity of the bleb contents. When apoptosis occurs in a microenvironment in direct contact with circulating plasma, the unique procoagulant consequences of the apoptotic surface may additionally be expressed. This might explain the increased incidence of pathological intravascular coagulation events that occur in some lupus patients who have anti-phospholipid antibodies.
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              Apoptosis in the vasculature: mechanisms and functional importance.

               A Tedgui,  Z Mallat (2000)
              Apoptotic death has now been recognized in a number of common and threatening vascular diseases, including atherosclerosis. Interest in apoptosis research relates to the fact that apoptosis, in contrast to oncosis, is a highly regulated process of cell death which raises the hope for the development of specific therapeutic strategies to alter disease progression. This review summarizes the mechanisms involved in vascular endothelial and smooth muscle cell survival/apoptosis, and the potential roles of apoptotic death in atherosclerosis and restenosis. The potential effects of modulation of apoptosis in these diseases are also discussed.
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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
                2005
                October 2005
                28 September 2005
                : 42
                : 5
                : 377-387
                Affiliations
                aCellular and Molecular Pathology Research Unit, Department of Oral Pathology and Oral Medicine, University of Sydney, Westmead Centre for Oral Health, bWestmead Millennium Institute, cElectron Microscope Laboratory, ICPMR, and dInstitute of Dental Research, Westmead Hospital, Westmead, Australia
                Article
                87213 J Vasc Res 2005;42:377–387
                10.1159/000087213
                16088211
                © 2005 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: 8, References: 25, Pages: 11
                Categories
                Research Paper

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