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      Adaptation of Skeletal Muscle Microvasculature to Increased or Decreased Blood Flow: Role of Shear Stress, Nitric Oxide and Vascular Endothelial Growth Factor

      a , b

      Journal of Vascular Research

      S. Karger AG

      Angiogenesis, Arterioles, Muscle activity, Ischaemia

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          Abstract

          This review elucidates the roles of capillary haemodynamics, nitric oxide (NO) and vascular endothelial growth factor (VEGF) in the remodelling of skeletal muscle microcirculation in response to increased (electrical stimulation) or decreased (chronic ischaemia) blood flow. During early stages of stimulation-induced angiogenesis, up-regulation of VEGF and its receptor VEGF receptor 2 is dependent on shear stress and NO release, whereas later, involvement of NO in the expanding capillary bed appears to be VEGF/VEGF receptor 2 independent. Arteriolar growth most likely relies on mechanical wall stresses while growth factor involvement is less clear. By contrast, in muscles with restricted blood flow, increased VEGF/VEGF receptor 2 expression after ischaemia onset is not associated with changes in shear stress or hypoxia, or capillary growth. After several weeks, VEGF protein levels are lower than normal while modest angiogenesis takes place, a temporal mismatch that limits the utility of using growth factor levels during ischaemia to assess angiogenic potential. Chronic stimulation of ischaemic muscles restores their depressed endothelial-dependent arteriolar dilatation, increases capillary shear stress and VEGF receptor 2 and promotes capillary growth. In patients with peripheral vascular disease, electrical stimulation of ischaemic calf muscles increases blood flow, capillary surface area and muscle performance, offering an alternative ‘endogenous’ treatment to gene or cell therapy.

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          Most cited references 48

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          Angiopoietins: a link between angiogenesis and inflammation.

          The angiopoietin (Ang)-Tie ligand-receptor system has a key regulatory role in regulating vascular integrity and quiescence. Besides its role in angiogenesis, it is an important regulator in numerous diseases including inflammation. Ang-1-mediated Tie2 activation is required to maintain the quiescent resting state of the endothelium. Agonistic Ang-1 functions are antagonized by Ang-2, which is believed to inhibit Ang-1-Tie2 signaling. Ang-2 destabilizes the quiescent endothelium and primes it to respond to exogenous stimuli, thereby facilitating the activities of inflammatory (tumor necrosis factor and interleukin-1) and angiogenic (vascular endothelial growth factor) cytokines. Intriguingly, Ang-2 is expressed weakly by the resting endothelium but becomes strongly upregulated following endothelial activation. Moreover, endothelial cells store Ang-2 in Weibel-Palade bodies from where it can be made available quickly following stimulation, suggesting a role of Ang-2 in controlling rapid vascular adaptive processes. This suggests that Ang-2 is the dynamic regulator of the Ang-Tie2 axis, thereby functioning as a built-in switch controlling the transition of the resting quiescent endothelium towards the activated responsive endothelium.
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            Collateral circulation

            Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.
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              PGC-1 coactivators and skeletal muscle adaptations in health and disease.

               Zolt Arany (2008)
              Skeletal muscle adapts to physiological demands by altering a number of programs of gene expression, including those driving mitochondrial biogenesis, angiogenesis, and fiber composition. Recently, the PGC-1 transcriptional coactivators have emerged as key players in the regulation of these adaptations. Many signaling cascades important in muscle physiology impinge directly on PGC-1 expression or activity. In turn, the PGC-1s powerfully activate many of the programs of muscle adaptation. These findings have implications for our understanding of muscle responses to physiological conditions like exercise, as well as in pathological conditions such as cachexia, dystrophy, and peripheral vascular disease.
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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
                2009
                August 2009
                26 June 2009
                : 46
                : 5
                : 504-512
                Affiliations
                aDepartment of Physiology, Division of Medicine, and bSchool of Sport and Exercise Sciences, University of Birmingham, Birmingham, UK
                Article
                226127 J Vasc Res 2009;46:504–512
                10.1159/000226127
                19556804
                © 2009 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: 2, References: 78, Pages: 9
                Categories
                Vascular Update

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