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      Pulse Pressure-Induced Transmural Fluid Flux Increases Bovine Aortic Smooth Muscle Cell Apoptosis in a Mitogen Activated Protein Kinase Dependent Manner

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          Abstract

          Background: Mechanical forces associated with blood flow are critical in the regulation of vascular smooth muscle cell (VSMC) growth, migration, differentiation and apoptosis as fundamental features in the pathogenesis of vascular disease. We investigated the effect of pulse pressure on VSMC apoptosis. Methods: Using a perfused transcapillary co-culture system, bovine thoracic aortic SMC (BASMC) were exposed to increases in pulsatile flow (0.3–17 ml/min) and hence pulse pressure (amplitude of pulse 6–50 mm Hg) in the absence or presence of bovine aortic endothelial cells (BAEC). The extent of apoptosis was determined by measuring caspase-3 activity, the levels of pro- and anti-apoptotic Bcl-2 family proteins, FasL and cellular apoptosis susceptibility (CAS) protein expression and the extent of DNA fragmentation. Results: Changes in pulse pressure resulted in a significant force- and time-dependent increase in caspase-3 activity in BASMC. This effect was maximal after 6 h, independent of BAEC presence, and attenuated following inhibition of mitogen-activated protein kinase (MAPK) activity with PD98059. In parallel cultures, there was a significant increase in Bad and Bax expression, concomitant with an increase in DNA fragmentation, and a significant decrease in Bcl-2 and Bcl-X<sub>L</sub> expression. The pro-apoptotic effects of pulse pressure were specific for differentiated cells but independent of p53, inasmuch as FasL and CAS expression were enhanced in differentiated adult cells but decreased in de-differentiated embryonic cells in response to flow. Conclusions: These results suggest that pulse pressure promotes phenotypically distinct VSMC apoptosis in vitro in an endothelial-independent, MAPK-dependent, manner.

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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
          : 364-374
          Affiliations
          aVascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin, Ireland; Departments of Surgery, bUniversity of Rochester Medical Center, Rochester, N.Y., and cGeorgetown University Medical Center, Georgetown University, Washington, D.C., USA
          Article
          80700 J Vasc Res 2004;41:364–374
          10.1159/000080700
          15353892
          © 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: 7, Tables: 1, References: 48, Pages: 11
          Categories
          Research Paper

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