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      Plasminogen Activator Expression Correlates with Genetic Differences in Vascular Remodeling

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          Abstract

          Intima-media thickening (IMT) of the carotid artery, a form of vascular remodeling, correlates well with coronary artery disease risk in humans. Vascular remodeling in response to blood flow is a complex process that critically involves altered cell matrix interactions. To gain insight into these events, we performed partial carotid ligation (left carotid (LCA) = low flow and right carotid (RCA) = high flow) in 2 inbred mouse strains: C57Bl/6J (C57) and FVB/NJ (FVB). To evaluate the role of the 2 major matrix-degrading systems, plasminogen activators (PAs) and matrix metalloproteinases (MMPs), we compared the expression of u-PA, t-PA, MMP-2 and MMP-9 in ligated carotids of C57 and FVB mice. The extent of remodeling was greater in response to low LCA than high RCA flow. Despite a similar decrease in LCA flow in both strains, maximal IMT volume was greater in FVB (82 ± 7 × 10<sup>–6</sup> µm<sup>3</sup>) than in C57 (38 ± 4 × 10<sup>–6</sup> µm<sup>3</sup>) after ligation. Among PAs and MMPs, increased expression of t-PA and u-PA correlated with increased IMT (p < 0.0005 and p < 0.001, respectively). MMP-2, MMP-9 and tissue inhibitors of metalloproteinase-2 expression also increased, but did not differ between strains. In summary, flow-induced IMT of the carotid is genetically determined and correlates with t-PA and u-PA expression in 2 inbred mouse strains.

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          Most cited references 12

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          Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent

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            Flow-induced vascular remodeling in the mouse: a model for carotid intima-media thickening.

            Vascular remodeling of the carotid artery with intima-media thickness (IMT) is an important predictive factor for human cardiovascular disease. We characterized a mouse model of vascular remodeling. The left external and internal carotid branches were ligated so that left carotid blood flow was reduced to flow via the occipital artery. In response to partial ligation of the left carotid artery (LCA), blood flow significantly decreased (-90%) in the LCA and increased (+70%) in the right carotid artery (RCA). Morphometry showed that both RCA and LCA underwent outward remodeling that was maximal at one week. Remodeling was greater in the RCA with predominantly increased lumen and very little increase in media or adventitia. In the LCA there was a dramatic increase in media with adventitia growth and intima formation. Correlation analysis indicated that the outward remodeling was more likely due to primary changes in the vessel wall rather than to changes in the lumen, such as shear stress. Mechanistic studies suggested roles for macrophage infiltration, upregulation of matrix metalloproteinase (MMP)-9, extracellular matrix reorganization, and vascular smooth muscle cell proliferation in LCA remodeling. The mouse model described here may be useful to define genetic determinants of IMT and identify new targets for therapy based on vascular remodeling.
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              Heritability of carotid artery intima-medial thickness in type 2 diabetes.

              Carotid artery intima-medial thickness (IMT), a marker of subclinical atherosclerosis, is a strong predictor of subsequent cardiovascular morbidity. The role of genetic factors in thickening of the carotid wall remains largely unknown. We hypothesize that in families with multiple members having diabetes, carotid IMT is likely to be associated with both inherited and environmental factors. To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, we studied 252 individuals with type 2 diabetes (mean age 60.6 years) from 122 families. Common carotid artery IMT was measured by high-resolution B-mode ultrasonography. Other measured factors included lipid levels, body mass index, fasting glucose, hemoglobin A1c, albumin/creatinine ratio, and self-reported medical history. Heritability estimates were obtained by using variance component methodology, as implemented in the SOLAR software package. Tests for association between carotid IMT and variables were performed by using mixed model analysis while accounting for the correlation due to family structure. The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 0.32 (SE 0.17, P=0.02). Further adjustment for total cholesterol, hypertension status, and current smoking status resulted in a heritability estimate of 0.41 (SE 0.16, P=0.004). The strongest predictors of carotid IMT, after adjusting for age and sex, were ethnicity (African American versus white), total cholesterol, and smoking status. These data provide empirical evidence that subclinical cardiovascular disease has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.
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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
                2004
                December 2004
                03 December 2004
                : 41
                : 6
                : 481-490
                Affiliations
                aCenter for Cardiovascular Research, Aab Institute of Biomedical Sciences and Department of Medicine, University of Rochester, Rochester, N.Y., USA; bMolecular Endocrinology Laboratory, Institute of Experimental Cardiology, Russian Cardiology Research and Production Center, and cMoscow State University, Moscow, Russia
                Article
                81804 J Vasc Res 2004;41:481–490
                10.1159/000081804
                15528930
                © 2004 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: 6, Tables: 4, References: 31, Pages: 10
                Categories
                Research Paper

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