This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 96/5/583    most recent 01.RES.0000158963.37132.8bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chai, S. Articles by Wogensen, L. Search for Related Content PubMed PubMed Citation Articles by Chai, S. Articles by Wogensen, L. Related Collections Pathophysiology Genetically altered mice Type 1 diabetes Type 2 diabetes Other Vascular biology

(Circulation Research. 2005;96:583.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Overexpression of Hyaluronan in the Tunica Media Promotes the Development of Atherosclerosis

Song Chai, Qing Chai, Carl C. Danielsen, Peter Hjorth, Jene R. Nyengaard, Thomas Ledet, Yu Yamaguchi, Lars M. Rasmussen, Lise Wogensen

From the Research Laboratory for Biochemical Pathology (S.C., Q.C., T.L., L.W.), Electron Microscopy and Stereological Research Laboratory (J.R.N.), and the Department of Clinical Biochemistry (L.M.R.), Aarhus University Hospital, Denmark; the Institute of Anatomy (C.C.D.) and the Institute of Molecular and Structural Biology (P.H.), University of Aarhus, Denmark; and The Burnham Institute (Y.Y.), La Jolla, Calif.

Correspondence to Lise Wogensen Bach, DMSci, Associate Professor, The Research Laboratory for Biochemical Pathology, Aarhus University Hospital, 44-Noerrebrogade, DK-8000 Aarhus C, Denmark. E-mail lwb{at}ki.au.dk

The arterial content of hyaluronan (HA) undergoes diffuse changes as part of the diabetic macroangiopathy. Because HA influences the phenotype of vascular cells in vitro such as proliferation, migration, and secretion, it is tempting to speculate that diabetes-induced hastened cardiovascular disease may be linked to the increased amount of HA. To explore the pathophysiological role of altered HA content in the arterial wall in vivo, we created transgenic (Tg) mice with HA overexpression in smooth muscle cells (SMCs) in large and small vessels, targeted by the smooth-muscle-cell-actin (SMA) promoter fused to the human hyaluronan synthase 2 (hHAS2) cDNA. RT-PCR demonstrated hHAS2 mRNA expression in the tunica media of large and small vessels. In situ hybridization confirmed that hHAS2 mRNA was targeted to the SMCs. The aortic HA content was elevated in the Tg mice, and by immunohistochemistry, it was seen that HA accumulated in the tunica media. The secretory profile of high- and low-molecular HA was similar in wild-type and Tg animals. Overproduction of HA in the aorta resulted in thinning of the elastic lamellae in Tg mice. Our data suggest that this may lead to increased mechanical stiffness and strength, as determined by controlled stretching until failure. Finally, overproduction of HA on the genetic background of the ApoE-deficient mouse strain promoted atherosclerosis development in the aorta. These results indicate that a single component of the diabetic macroangiopathy, diffuse accumulation of HA, accelerates the progression of atherosclerosis.

Key Words: hyaluronan • biomechanics • atherosclerosis • diabetes • transgenic

This article has been cited by other articles:

				D. Vigetti, M. Rizzi, M. Viola, E. Karousou, A. Genasetti, M. Clerici, B. Bartolini, V. C Hascall, G. De Luca, and A. Passi The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells Glycobiology, May 1, 2009; 19(5): 537 - 546. [Abstract] [Full Text] [PDF]

				B. J. Bennett, S. S. Wang, X. Wang, X. Wu, and A. J. Lusis Genetic Regulation of Atherosclerotic Plaque Size and Morphology in the Innominate Artery of Hyperlipidemic Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2009; 29(3): 348 - 355. [Abstract] [Full Text] [PDF]

				S. W. Sakr, S. Potter-Perigo, M. G. Kinsella, P. Y. Johnson, K. R. Braun, Y. Goueffic, M. E. Rosenfeld, and T. N. Wight Hyaluronan Accumulation Is Elevated in Cultures of Low Density Lipoprotein Receptor-deficient Cells and Is Altered by Manipulation of Cell Cholesterol Content J. Biol. Chem., December 26, 2008; 283(52): 36195 - 36204. [Abstract] [Full Text] [PDF]

				E. Papakonstantinou, F. M. Kouri, G. Karakiulakis, I. Klagas, and O. Eickelberg Increased hyaluronic acid content in idiopathic pulmonary arterial hypertension Eur. Respir. J., December 1, 2008; 32(6): 1504 - 1512. [Abstract] [Full Text] [PDF]

				N. Itano Simple Primary Structure, Complex Turnover Regulation and Multiple Roles of Hyaluronan J. Biochem., August 1, 2008; 144(2): 131 - 137. [Abstract] [Full Text] [PDF]

				J. Zhou, G. H. Werstuck, S. Lhotak, Y. Y. Shi, V. Tedesco, B. Trigatti, J. Dickhout, A. K. Majors, P. M. DiBello, D. W. Jacobsen, et al. Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice FASEB J, July 1, 2008; 22(7): 2569 - 2578. [Abstract] [Full Text] [PDF]

				L. Zhao, E. Lee, A. M. Zukas, M. K. Middleton, M. Kinder, P. S. Acharya, J. A. Hall, D. J. Rader, and E. Pure CD44 Expressed on Both Bone Marrow-Derived and Non-Bone Marrow-Derived Cells Promotes Atherogenesis in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1283 - 1289. [Abstract] [Full Text] [PDF]

				S. Misra, L. M. Obeid, Y. A. Hannun, S. Minamisawa, F. G. Berger, R. R. Markwald, B. P. Toole, and S. Ghatak Hyaluronan Constitutively Regulates Activation of COX-2-mediated Cell Survival Activity in Intestinal Epithelial and Colon Carcinoma Cells J. Biol. Chem., May 23, 2008; 283(21): 14335 - 14344. [Abstract] [Full Text] [PDF]

				D. Vigetti, M. Viola, E. Karousou, M. Rizzi, P. Moretto, A. Genasetti, M. Clerici, V. C. Hascall, G. De Luca, and A. Passi Hyaluronan-CD44-ERK1/2 Regulate Human Aortic Smooth Muscle Cell Motility during Aging J. Biol. Chem., February 15, 2008; 283(7): 4448 - 4458. [Abstract] [Full Text] [PDF]

				B. C. Capell, F. S. Collins, and E. G. Nabel Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes Circ. Res., July 6, 2007; 101(1): 13 - 26. [Abstract] [Full Text] [PDF]

				J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]

				Y. Goueffic, C. Guilluy, P. Guerin, P. Patra, P. Pacaud, and G. Loirand Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation Cardiovasc Res, November 1, 2006; 72(2): 339 - 348. [Abstract] [Full Text] [PDF]

				T. Raj, P. Kanellakis, G. Pomilio, G. Jennings, A. Bobik, and A. Agrotis Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1845 - 1851. [Abstract] [Full Text] [PDF]

				M. van den Boom, M. Sarbia, K. von Wnuck Lipinski, P. Mann, J. Meyer-Kirchrath, B.H. Rauch, K. Grabitz, B. Levkau, K. Schror, and J.W. Fischer Differential Regulation of Hyaluronic Acid Synthase Isoforms in Human Saphenous Vein Smooth Muscle Cells: Possible Implications for Vein Graft Stenosis Circ. Res., January 6, 2006; 98(1): 36 - 44. [Abstract] [Full Text] [PDF]