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      Intracellular pH in the Resistance Vasculature: Regulation and Functional Implications


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          Net acid extrusion from vascular smooth muscle (VSMCs) and endothelial cells (ECs) in the wall of resistance arteries is mediated by the Na<sup>+</sup>,HCO<sub>3</sub><sup>–</sup> cotransporter NBCn1 ( SLC4A7) and the Na<sup>+</sup>/H<sup>+</sup> exchanger NHE1 ( SLC9A1) and is essential for intracellular pH (pH<sub>i</sub>) control. Experimental evidence suggests that the pH<sub>i</sub> of VSMCs and ECs modulates both vasocontractile and vasodilatory functions in resistance arteries with implications for blood pressure regulation. The connection between disturbed pH<sub>i</sub> and altered cardiovascular function has been substantiated by a genome-wide association study showing a link between NBCn1 and human hypertension. On this basis, we here review the current evidence regarding (a) molecular mechanisms involved in pH<sub>i</sub> control in VSMCs and ECs of resistance arteries at rest and during contractions, (b) implications of disturbed pH<sub>i</sub> for resistance artery function, and (c) involvement of disturbed pH<sub>i</sub> in the pathogenesis of vascular disease. The current evidence clearly implies that pH<sub>i</sub> of VSMCs and ECs modulates vascular function and suggests that disturbed pH<sub>i</sub> either consequent to disturbed regulation or due to metabolic challenges needs to be taken into consideration as a mechanistic component of artery dysfunction and disturbed blood pressure regulation.

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          The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis.

          Recent research has highlighted the fundamental role of the tumour's extracellular metabolic microenvironment in malignant invasion. This microenvironment is acidified primarily by the tumour-cell Na(+)/H(+) exchanger NHE1 and the H(+)/lactate cotransporter, which are activated in cancer cells. NHE1 also regulates formation of invadopodia - cell structures that mediate tumour cell migration and invasion. How do these alterations of the metabolic microenvironment and cell invasiveness contribute to tumour formation and progression?
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            Reactive species mechanisms of cellular hypoxia-reoxygenation injury.

            Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular hypoxia and reoxygenation are two essential elements of ischemia-reperfusion injury. Activated neutrophils contribute to vascular reperfusion injury, yet posthypoxic cellular injury occurs in the absence of inflammatory cells through mechanisms involving reactive oxygen (ROS) or nitrogen species (RNS). Xanthine oxidase (XO) produces ROS in some reoxygenated cells, but other intracellular sources of ROS are abundant, and XO is not required for reoxygenation injury. Hypoxic or reoxygenated mitochondria may produce excess superoxide (O) and release H(2)O(2), a diffusible long-lived oxidant that can activate signaling pathways or react vicinally with proteins and lipid membranes. This review focuses on the specific roles of ROS and RNS in the cellular response to hypoxia and subsequent cytolytic injury during reoxygenation.
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              Proton-sensing G-protein-coupled receptors.

              Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8-site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2012
                18 August 2012
                : 49
                : 6
                : 479-496
                Department of Biomedicine and Water and Salt Research Center, Aarhus University, Aarhus, Denmark
                Author notes
                *Dr. Ebbe Boedtkjer, Department of Biomedicine, Aarhus University, Ole Worms Allé 6, Building 1180, DK–8000 Aarhus C (Denmark), Tel. +45 8716 7283, E-Mail eb@fi.au.dk
                341235 J Vasc Res 2012;49:479–496
                © 2012 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.

                : 17 April 2012
                : 20 June 2012
                Page count
                Figures: 7, Pages: 18

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Endothelial cells,Hypertension,Hypoxia-reoxygenation,Resistance arteries,Vasorelaxation, SLC9A1 ,Vasoconstriction, SLC4A7 ,Nitric oxide,Vascular smooth muscle cells


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