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Mechanical and Pharmacological Approaches to Investigate the Pathogenesis of Marfan Syndrome in the Abdominal Aorta
Abstract
Background: Occurrence of disease complications in the abdominal aorta in Marfan syndrome, a connective tissue disorder caused by mutations in the gene encoding fibrillin-1, is relatively rare. We hypothesized that Marfan syndrome could affect the structure, vasomotor function and mechanical property of the abdominal aorta. Methods and Results: Abdominal aorta from mice at 3, 6, 9 and 12 months of age, heterozygous for the Fbn1 allele encoding a cysteine substitution ( Fbn1<sup>C1039G/+</sup>, Marfan mice, n = 50), were compared with those from age-matched control littermates (n = 50). Marfan abdominal aorta demonstrated pronounced elastic fiber degradation and disorganization, concomitant with an increased aortic stiffness during aging. In the isometric force measurement, vasoconstriction in response to membrane depolarization or phenylephrine stimulation was similar in both Marfan and control abdominal aorta. However, Marfan abdominal aorta was less sensitive to the inhibition of the phenylephrine-induced contraction by indomethacin and SQ-29548, during which the release of thromboxane A<sub>2</sub> was one half of that of the controls. Nevertheless, the protein expression of cyclooxygenase-1 and cyclooxygenase-2 detected by Western immunoblotting was not different between the 2 strains. Conclusions: We demonstrated that Marfan syndrome affected abdominal aorta with respect to matrix elastic fiber organization, aortic stiffness and release of thromboxane A<sub>2</sub>.
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Most cited references 22
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Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome.
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TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome
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Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome
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113603 J Vasc Res 2008;45:314–322Copyright: 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.