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      Adaptation of Hindquarter Vascular Reactivity to Femoral Artery Ligation and Hypercholesterolemia in the Rabbit

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          Abstract

          Aims: The effects of ischemia and hypercholesterolemia on the function and morphological adaptation of the rabbit hindlimb were assessed. Methods: In rabbits on normal or cholesterol diet, experiments were performed on days 0–28 following bilateral femoral artery ligation. Calf blood pressure (C<sub>BP</sub>), exercise tolerance, flow reserve, agonist vasodilatation, angiography and capillary density were examined and modeled. Results: C<sub>BP</sub> decreased markedly post-ligation and returned to 41 and 68% of baseline by days 7 and 28. Exercise tolerance was attenuated 40% and flow reserve 50–60% on day 7, with recovery by day 28. Ligation caused decreases in 5-hydroxytryptamine-induced dilatation, while adenosine and acetylcholine responses were unaffected. Hypercholesterolemia attenuated acetylcholine-elicited dilatation. There was marked loss of adenosine dilatation on days 7–14 in the ligation plus hypercholesterolemia group. Ligation caused a doubling in the number of medium-sized collateral arteries. Hypercholesterolemia, either alone or combined with ligation, greatly augmented small vessel density. Capillary density was unaltered by any treatment. Conclusions: The rabbit hindlimb shows a remarkable ability to recover its muscle function through vascular adaptation and remodeling 4 weeks following ligation, with or without hypercholesterolemia. Exercise tolerance, flow reserve and vascular reactivity were mainly restored 28 days post-ligation.

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          Most cited references 19

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          Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

          Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.
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            Time course of arteriogenesis following femoral artery occlusion in the rabbit.

            We examined the time course of arteriogenesis (collateral artery growth) after femoral artery ligation and the effect of monocyte chemoattractant protein-1 (MCP-1). New Zealand White rabbits received MCP-1 or phosphate buffered saline (PBS) for a 1-week period, either directly or 3 weeks after femoral artery ligation (non-ischemic model). A control group was studied with intact femoral arteries and another 1 min after acute femoral artery ligation. Collateral conductance index significantly increased when MCP-1 treatment started directly after femoral artery ligation (acute occlusion: 0.94+/-0.19; without occlusion: 168.56+/-15.99; PBS: 4.10+/-0.48; MCP-1: 33.96+/-1.76 ml/min/100 mmHg). However, delayed onset of treatment 3 weeks after ligation and final study of conductance at 4 weeks showed no significant difference against a 4-week control (PBS: 79.08+/-7.24; MCP-1: 90.03+/-8.73 ml/min/100 mmHg). In these groups increased conductance indices were accompanied by a decrease in the number of visible collateral vessels (from 18 to 36 identifiable vessels at day 7 to about four at 21 days). We conclude that the chemokine MCP-1 markedly accelerated collateral artery growth but did not alter its final extent above that reached spontaneously as a function of time. We show thus for the first time that a narrow time window exists for the responsiveness to the arteriogenic actions of MCP-1, a feature that MCP-1 may share with other growth factors. We show furthermore that the spontaneous adaptation by arteriogenesis stops when only about 50% of the vasodilatory reserve of the arterial bed before occlusion are reached. The superiority of few large arterial collaterals in their ability to conduct large amounts of blood flow per unit of pressure as compared to the angiogenic response where large numbers of small vessels are produced with minimal ability to allow mass transport of bulk flow is stressed.
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              Repeated measurements and multiple comparisons in cardiovascular research.

               J Ludbrook (1994)
              In cardiovascular research, experiments are commonly performed in which repeated measurements are made in the same individual at predetermined intervals of time or at ascending levels of stimulus or dose of drug. The goal is usually to test the effects of treatments or disease state on the time course of the response, or on the stimulus-response relationship. Since the passage of time or the order of stimuli or doses is fixed, statistical analysis of the results of such experiments is associated with an excessive risk of false positive interferences (type I error) unless special precautions are taken. The nature of the statistical problems associated with repeated measures experimental designs, and several solutions to them, have been discussed. An approach much favoured by cardiovascular investigators is to make multiple pairwise contrasts between treatments at each time or dose, or between times or doses within each treatment. This greatly inflates the risk of type I error unless special precautions are taken, and the information provided by making multiple contrasts is of limited value. I believe that repeated measures analysis of variance, with a correction for multisample asphericity, usually provides the most informative and least biased test of the biological hypotheses proposed by cardiovascular investigators. Other analytical techniques, such as comparing areas under curves and regression analysis, have also been discussed. Summary recommendations are given in the table.
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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
                2008
                June 2008
                22 January 2008
                : 45
                : 4
                : 279-294
                Affiliations
                Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Melbourne, Vic., Australia
                Article
                113600 J Vasc Res 2008;45:279–294
                10.1159/000113600
                18212510
                © 2008 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, Tables: 2, References: 38, Pages: 16
                Categories
                Research Paper

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