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      High-Flow-Induced Arterial Remodeling in Rats with Different Susceptibilities to Cerebral Aneurysms


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          Background: The higher incidence of cerebral aneurysms (CAs) induced by enhanced arterial blood flow in Long Evans (LE) compared to Brown Norway (BN) rats suggests that intrinsic differences in high-flow arterial remodeling may be involved in determining CA susceptibility. Some aspects of this remodeling were compared in LE and BN rats after creation of an abdominal aortocaval fistula (ACF). Methods and Results: At 4 days with ACF, aortic luminal cross-sectional area (LCSA) determined by morphometry was increased by 20% in LE but not in BN rats. mRNA levels, determined by RT-PCR, were higher in LE than in BN rats for collagen α1(I), collagen α1(III), MMP2 and its inhibitor TIMP1 at 19 days with ACF. Nitric oxide synthase (NOS) mRNA levels were higher in LE rats at 4 days for the inducible (NOS2) isoform and at 4 and 19 days for the neuronal (NOS1) isoform. Aortic LCSA and NOS1 mRNA levels were tightly correlated and NOS inhibition prevented ACF-induced aortic remodeling in the LE rat. MMP2 and MMP7 activity, evaluated by zymography at 4 days with ACF, did not greatly differ between BN and LE. Conclusions: These data suggest that a higher intrinsic ability for high-flow-induced arterial enlargement associated with NOS gene overexpression may be a possible genetic determinant in CA susceptibility.

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          Matrix metalloproteinase-9 in cerebral aneurysms.

          Generalized disruption of arterial wall morphological changes in patients harboring cerebral aneurysms has been documented; however, little is known regarding the pathogenesis of these changes. To explore the role of the elastolytic gelatinase, matrix metalloproteinase-9 (MMP-9), levels of this enzyme in the wall of intracranial aneurysms were compared with those in both intracranial and extracranial arteries. The tissue levels of its major inhibitor, tissue inhibitor of metalloproteinase (TIMP), were measured in these tissues as well. The activity of MMP-9 in plasma was also evaluated. The aneurysm wall was excised from three of six patients undergoing craniotomies for aneurysm clipping. A 1-cm segment of superficial temporal artery (STA) was obtained from each of six patients. Additional STAs were obtained from six patients in the control group who were undergoing craniotomies for nonvascular disease. An intracranial artery was also obtained from the anterior temporal neocortical resection of a patient undergoing a craniotomy for mesial temporal sclerosis. MMP-9 and TIMP levels were determined via Western blot analysis. Using substrate gel Zymography, MMP-9 plasma activity was determined for a separate cohort of patients with aneurysms (n = 6) and patients in the control group (n = 6). MMP-9 and TIMP levels in the aneurysm wall were markedly increased beyond levels in both extracranial arteries (STAs from patients with aneurysms and patients in the control group) and the intracranial artery. There were no differences in the levels of MMP-9 in the STAs of patients harboring aneurysms when compared with patients in the control group. Also, no differences were noted in plasma MMP-9 activity. Local rather than systemic perturbations in MMP-9 levels may contribute to the matrix disruption associated with cerebral aneurysms. This local up-regulation is not the result of TIMP down-regulation. The lack of increased systemic metalloproteinase activity precludes the use of plasma MMP-9 activity as a screening tool for presymptomatic aneurysms. However, local therapeutic modulation of MMP-9 activity may help arrest aneurysm progression.
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            Disruption of gene for inducible nitric oxide synthase reduces progression of cerebral aneurysms.

            The rupture of a cerebral aneurysm is a major cause of subarachnoid hemorrhage, but the mechanism of its development remains unclear. Inducible nitric oxide synthase (iNOS) is expressed in human and rat cerebral aneurysms, and aminoguanidine, a relatively selective inhibitor of iNOS, can decrease the number of the aneurysms in rats. In this study we applied our new mouse model of cerebral aneurysms to the iNOS gene knockout mice and observed experimental cerebral aneurysms in these animals to elucidate the role of iNOS in the process of cerebral aneurysm formation. Eight C57/Bl6 mice and 16 iNOS knockout mice received a cerebral aneurysm induction procedure. Four months after the operation, the mice were killed, their cerebral arteries were dissected, and the region of the bifurcation of the anterior cerebral artery/olfactory artery was examined histologically and immunohistochemically. No significant difference was seen in the incidence of cerebral aneurysms between iNOS+/+ and iNOS-/- mice. However, the size of advanced cerebral aneurysms and the number of apoptotic smooth muscle cells were significantly greater in iNOS+/+ mice than in iNOS-/- mice. Inducible NOS is not necessary for the initiation of cerebral aneurysm. However, the results of this study suggest that regulation of iNOS may have therapeutic potential in the prevention of the progression of cerebral aneurysms.
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              Strain-dependent vascular remodeling: the "Glagov phenomenon" is genetically determined.

              Atherosclerosis of the carotid artery, called intima-media thickening (IMT), is a form of vascular remodeling that is an important predictor for cardiovascular events and has a strong genetic component. Recently, we established a mouse model of vascular remodeling based on partial ligation of the carotid, which is relevant to the "Glagov phenomenon." We hypothesized that there would be genetically determined differences in outward remodeling and IMT induced by carotid flow alterations. We compared vascular remodeling among 5 inbred strains of mice. Despite similar changes in flow among the strains in the left carotid artery (LCA), we observed dramatic differences in remodeling of the partially ligated LCA relative to control. The smallest IMT volume (26+/-3 microm3) was found in C3H/HeJ mice, and the largest were in SJL/J (59+/-10 microm3) and FVB/NJ (81+/-6 microm3). Shear stress did not differ after ligation among strains. Lumen area decreased only when stenosis was > or =55%. IMT correlated significantly with outward remodeling among inbred strains (except C3H). There were significant strain-dependent differences in remodeling index (measured as vessel area/IMT), which suggest fundamental alterations in sensing or transducing hemodynamic signals among strains. Among hemodynamic factors, low shear stress and high heart rate were predictive for IMT. Specifically, heart rate (bpm: C3H, 592+/-6; SJL, 649+/-6; FVB, 683+/-7) but not systolic blood pressure (mm Hg: C3H, 116+/-2; SJL, 119+/-1; FVB, 136+/-1) was predictive. The present study indicates that performing a genetic cross of these strains and total genome scan should identify genes that mediate vascular remodeling.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                May 2006
                17 May 2006
                : 43
                : 3
                : 217-228
                INSERM U698, Hôpital Xavier Bichat, Paris, France
                91101 J Vasc Res 2006;43:217–228
                © 2006 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.

                : 01 April 2005
                : 20 November 2005
                Page count
                Figures: 5, Tables: 1, References: 53, Pages: 12
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Aneurysms, rat,Arterial remodeling,Blood flow,Nitric oxide synthase


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