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      Mechanisms of Flow-Mediated Signal Transduction in Endothelial Cells: Kinetics of ATP Surface Concentrations

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          Abstract

          Intracellular free calcium ([Ca<sup>2+</sup>]<sub>i</sub>) was measured in single cells of a confluent endothelial monolayer subjected to defined flow. Flow medium containing adenosine triphosphate (ATP) was used to study the influence of flow forces upon agonist-response coupling as mediated via the P2<sub>y</sub>-purinoceptor. [Ca<sup>2+</sup>]<sub>i</sub> responses were highly sensitive to the fluid motion at the cell surface; consecutive small increases of flow stimulated large [Ca<sup>2+</sup>]i transients with the levels returning to baseline at the new flow rate within 250 s. The characteristics of [Ca<sup>2+</sup>]<sub>i</sub> transients were also influenced by decreasing flow. Since potent ecto-nucleotidases at the endothelial cell surface rapidly degrade ATP, we postulated that a combination of flow and degradative enzymes regulates the mass transport of ATP in the boundary layer. The hypothesis predicts that step increases of flow exceed the capacity of the ectonucleotidases and allow ATP to reach the receptor. Experiments were conducted to compare ATP and ADP<sub>β</sub>S, a nonhydrolyzable ATP analog that resists degradation by surface ectonucleotidases, and calculations of ATP mass transport to the cell surface were compared to estimates of surface clearance rates. Calculations of mass transport coefficients for ATP in the boundary layer demonstrated that changes of flow which elicited a prominent [Ca<sup>2+</sup>]<sub>i</sub> response represented 26-73 % changes in the mass transport of ATP from the bulk fluid. When steady-state mass transport coefficients for ATP under various flow conditions were compared with the estimated rate constant for surface degradation of ATP, ratios close to unity were obtained. These results suggest that both boundary layer mass transport and ATP clearance rates can be rate-limiting for flow-mediated activation of the P<sub>2y</sub>-receptor. The experiments provide evidence for differential signal transduction responses in the endothelium driven by diffusion gradients (derived from both the blood and the vessel wall), which are likely to vary widely in the complex flow fields encountered in vivo.

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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
          1992
          1992
          23 September 2008
          : 29
          : 6
          : 410-419
          Affiliations
          aPritzker School of Medicine, The University of Chicago, Department of Pathology, Chicago, Ill.; bThe Pennsylvania State University, Department of Chemical Engineering, University Park, Pa., USA
          Article
          158959 J Vasc Res 1992;29:410–419
          10.1159/000158959
          1489886
          © 1992 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
          Pages: 10
          Categories
          Research Paper

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