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.

Keywords:
Aneurysms, rat, Arterial remodeling, Nitric oxide synthase, Blood flow
1.
Langille BL: Arterial remodeling: relation to hemodynamics. Can J Physiol Pharmacol 1996;74:834–841.
2.
Wolinsky H: Long-term effects of hypertension on the rat aortic wall and their relations to concurrent aging changes. Circ Res 1972;30:301–309.
3.
Ben Driss A, Benessiano J, Poitevin P, Levy B, Michel JB: Arterial expansive remodeling induced by high flow rates. Am J Physiol 1997;272:H851–H858.
4.
Miyashiro JK, Poppa V, Berk BC: Flow-induced vascular remodeling in the rat carotid artery diminishes with age. Circ Res 1997;81:311–319.
5.
Zarins CK, Zatina MA, Giddens DP, Ku DN, Glagov S: Shear stress regulation of artery lumen diameter in experimental atherogenesis. J Vasc Surg 1987;5:413–420.
6.
Wentzel JJ, Janssen E, Vos J, Schuurbiers JCH, Krams R, Serruys PW, de Feyter PJ, Slager CJ: Extension of increased atherosclerotic wall thickness into high shear stress regions is associated with loss of compensatory remodeling. Circulation 2003;108:17–23.
7.
Hashimoto N, Handa H, Nagata I, Hazama F: Saccular cerebral aneurysms in rats. Am J Pathol 1983;110:397–399.
8.
Hashimoto N, Handa H, Nagata I, Hazama F: Experimentally-induced cerebral aneurysm in rats. V. Relation of hemodynamics in the circle of Willis to formation of aneurysms. Surg Neurol 1980;13:41–45.
9.
Coutard M, Osborne-Pellegrin M: Genetic susceptibility to experimental cerebral aneurysm formation in the rat. Stroke 1997;28:1035–1042.
10.
Lehman M, Owens GK, Kassell NF, Hongo K: Mechanism of enlargement of major cerebral collateral arteries in rabbits. Stroke 1991;22:499–504.
11.
Kondo S, Hashimoto N, Kikuchi H, Hazama F, Nagata I, Kataoka H: Cerebral aneurysms arising at nonbranching sites. An experimental study. Stroke 1997;28:398–404.
12.
Sekhar LN, Heros RC: Origin, growth, and rupture of saccular aneurysms: a review. Neurosurgery 1981;8:248–260.
13.
Coutard M, Huang W, Osborne-Pellegrin M: Heritability of intracerebral hemorrhagic lesions and cerebral aneurysms in the rat. Stroke 2000;31:2678–2684.
14.
Singh TM, Abe KY, Sasaki T, Zhuang YJ, Masuda H, Zarins CK: Basic fibroblast growth factor expression precedes flow-induced arterial enlargement. J Surg Res 1998;77:165–173.
15.
Xu C, Lee S, Shu C, Masuda H, Zarins CK: Expression of TGF-β1 and β3 but not apoptosis factors relates to flow-induced arterial enlargement. BMC Cardiovasc Disord 2002;2:11.
16.
Hsieh HJ, Li NQ, Frangos JA: Shear stress increases endothelial platelet-derived growth factor mRNA levels. Am J Physiol 1991;260:H642–H646.
17.
Tronc F, Wassef M, Esposito B, Henrion D, Glagov S, Tedgui A: Role of NO in flow-loaded induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol 1996;16:1256–1262.
18.
Nadaud S, Philippe M, Arnal JF, Michel JB, Soubrier F: Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow. Circ Res 1996;79:857–863.
19.
Noris M, Morigi M, Donadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A: Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res 1995;76:536–543.
20.
Gosgnach W, Messika-Zeitoun D, Gonzalez W, Philippe M, Michel JB: Shear-stress induces iNOS expression in cultured smooth muscle cells; role of oxidative stress. Am J Physiol 2000;279:C1880–C1888.
21.
Papadaki M, Tilton RG, Eskin SG, McIntire LV: Nitric oxide production by cultured aortic smooth muscle cells: stimulation by fluid flow. Am J Physiol 1998;274:616–626.
22.
Loesch A, Burnstock G: Perivascular nerve fibers and endothelial cells of the rat basilar artery: immuno-gold labelling of antigenic sites for type I and type III nitric oxide synthase. J Neurocytol 1998;27:197–204.
23.
Huang A, Sun D, Shesely EG, Levee EM, Koller A, Kaley G: Neuronal NOS-dependent dilatation to flow in coronary arteries of male eNOS-KO mice. Am J Physiol 2002;282:H429–H436.
24.
Ceiler DL, De Mey JG: Chronic N(G)-nitro-L-arginine methyl ester treatment does not prevent flow-induced remodeling in mesenteric feed arteries and arcading arterioles. Arterioscler Thromb Vasc Biol 2000;20:2057–2063.
25.
Tronc F, Mallat Z, Lehoux S, Wassef M, Esposito B, Tedgui A: Role of metalloproteinases in blood flow-induced arterial enlargement: interaction with NO. Arterioscler Thromb Vasc Biol 2000;20:120–126.
26.
Bassiouny HS, Song RH, Hong XF, Singh A, Kocharyan H, Glagov S: Flow regulation of 72-kD collagenase IV (MMP-2) after experimental arterial injury. Circulation 1998;98:157–163.
27.
De Kleijn DP, Van der Zanden J, Schonveld AH, Rebel A: Matrix metalloproteinases 2 and 9 are differentially regulated during flow induced remodeling of rabbit femoral and carotid arteries. Circulation 1997;96(suppl):I-172.
28.
Abbruzzese TA, Guzman RJ, Martin RL, Yee C, Zarins CK, Dalman RL: Matrix metalloproteinase inhibition limits arterial enlargement in a rodent arteriovenous fistula model. Surgery 1998;124:328–335.
29.
Karwowsky JK, Markezich A, Whitson J, Abbruzzese TA, Zarins CK, Dalman RL: Dose-dependent limitation of arterial enlargement by the matrix metalloproteinase inhibitor RS-113.356. J Surg Res 1999;87:122–129.
30.
Sauvage M, Jacob MP, Osborne-Pellegrin M: Aortic elastin and collagen content and synthesis in two rat strains with different susceptibilities to the rupture of the internal elastic lamina. J Vasc Res 1997;34:126–136.
31.
Feldman LJ, Mazighi M, Scheuble A, Deux JF, De Benedetti E, Badier-Commander C, Brambilla E, Henin D, Steg G, Jacob MP: Differential expression of matrix metalloproteinases after stent implantation and balloon angioplasty in the hypercholesterolemic rabbit. Circulation 2001;103:3117–3122.
32.
Fontaine V, Jacob MP, Houard X, Rossignol P, Plissonnier D, Angles-Cano E, Michel JB: Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am J Pathol 2002;161:1701–1710.
33.
Osborne-Pellegrin MJ, Ingallina F, Coutard M, Michel JB: Spontaneous and high flow induced rupture of the internal elastic lamina in various arteries in different rat strains. Proceedings XIth International Vascular Biology meeting. J Submicrosc Cytol Pathol 2000;32:365.
34.
Ibrahim J, Miyashiro JK, Berk BC: Shear stress is differentially regulated among inbred rat strains. Circ Res 2003;92:1001–1009.
35.
Harmon K, Couper L, Lindner V: Strain-dependent vascular remodeling phenotypes in inbred mice. Am J Pathol 2000;156:1741–1748.
36.
Korshunov VA, Berk BC: Strain-dependent vascular remodeling. The ‘Glagov phenomenon’ is genetically determined. Circulation 2004;110:220–226.
37.
Medhora M, Bousamra M 2nd, Zhu D, Somberg L, Jacobs ER: Upregulation of collagens detected by gene array in a model of flow-induced pulmonary vascular remodeling. Am J Physiol 2002;282:H414–H422.
38.
Ishikawa Y, Asuwa N, Ishii T, Ito K, Akasaka Y, Masuda T, Zang L, Kiguchi H: Collagen alteration in vascular remodeling by hemodynamic factors. Virchows Arch 2000;437:138–148.
39.
Sluijter JP, Smeets MB, Velema E, Pasterkamp G, Kleijn DP: Increase in collagen turnover but not in collagen fiber content is associated with flow-induced arterial remodeling. J Vasc Res 2004;41:546–555.
40.
Ueba H, Kawakami M, Yaginuma T: Shear stress as an inhibitor of vascular smooth muscle cell proliferation. Role of transforming growth factor-β1 and tissue-type plasminogen activator. Arterioscler Thromb Vasc Biol 1997;17:1512–1516.
41.
Peters D, Kassam A, Feingold E, Heidrich-O’Hare E, Yonas H, Ferrell R, Brufsky A: Molecular anatomy of an intracranial aneurysm. Coordinated expression of genes involved in wound healing and tissue remodeling. Stroke 2001;32:1036–1042.
42.
Palumbo R, Gaetano C, Melillo G, Toschi E, Remuzzi A, Capogrossi MC: Shear stress downregulation of platelet-derived growth factor-β and matrix metalloprotinase-2 is associated with inhibition of smooth muscle cell invasion and migration. Circulation 2000;102:225–230.
43.
Kim SC, Singh M, Huang J, Presigiacomo CJ, Winfree CJ, Solomon RA, Connolly ES: Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 1997;41:642–647.
44.
Bruno G, Todor R, Lewis I, Chyatte D: Vascular extracellular matrix remodeling in cerebral aneurysms. J Neurosurg 1998;89:431–440.
45.
Pourageaud F, De Mey JG: Structural properties of rat mesenteric small arteries after 4-wk exposure to elevated or reduced blood flow. Am J Physiol 1997;273:H1699–H1706.
46.
Iizuka T, Oishi K, Sasaki M, Hatanaka Y, Minatogawa Y, Uemura S, Koike M: Nitric oxide and aneurysm formation in Kawasaki disease. Acta Paediatr 1997;86:470–473.
47.
Johanning JM, Franklin DP, Han DC, Carey DJ, Elmore JR: Inhibition of inducible nitric oxide synthase limits nitric oxide production and experimental aneurysm expansion. J Vasc Surg 2001;33:579–586.
48.
Lee JK, Borhani M, Ennis TL, Upchurch GR, Thompson RW: Experimental abdominal aortic aneurysms in mice lacking expression of inducible nitric oxide synthase. Arterioscler Tromb Vasc Biol 2001;21:1393–1401.
49.
Fukuda S, Hashimoto N, Naritomi H, Nagata I, Nozaki K, Kondo S, Kurino M, Kikuchi H: Prevention of rat cerebral aneurysm formation by inhibition of nitric oxide synthase. Circulation 2000;101:2532–2538.
50.
Sadasama N, Kazuhiko N, Hashimoto N: Disruption of gene for inducible nitric oxide synthase reduces progression of cerebral aneurysms. Stroke 2003;34:2980–2984.
51.
Benyo Z, Lacza Z, Hortdbagyi T, Gorlach C, Wahl M: Functional importance of neuronal nitric oxide synthase in the endothelium of rat basilar arteries. Brain Res 2000;277:79–84.
52.
Coutard M: Experimental cerebral aneurysms in the female heterozygous Blotchy mouse. Int J Exp Pathol 1999;80:357–367.
53.
Coutard M, Mertès P, Mairose P, Osborne-Pellegrin M, Michel JB: Arterial sympathetic innervation and cerebrovascular diseases in original rat models. Auton Neurosci 2003;104:137–145.
© 2006 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.