Published online before print November 6, 2008

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(American Journal of Pathology. 2008;173:1919-1928.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070875

Retrovirally Mediated Overexpression of Glycosaminoglycan-Deficient Biglycan in Arterial Smooth Muscle Cells Induces Tropoelastin Synthesis and Elastic Fiber Formation in Vitro and in Neointimae after Vascular Injury

Jin-Yong Hwang^*, Pamela Y. Johnson^*, Kathleen R. Braun^*, Aleksander Hinek, Jens W. Fischer, Kevin D. O’Brien^¶, Barry Starcher^||, Alexander W. Clowes^**, Mervyn J. Merrilees and Thomas N. Wight^*

From the Hope Heart Program,^* Benaroya Research Institute, Seattle, Washington; Department of Internal Medicine, Gyeong National University, Jinju, South Korea; Division of Cardiovascular Research, Hospital for Sick Children, Toronto, Ontario, Canada; Institut für Pharmakologie, Universitätsklinikum Essen, Germany; Division of Cardiology,^¶ University of Washington, Seattle, Washington; Department of Biochemistry,|| University of Texas Health Center at Tyler, Tyler, Texas; Division of Vascular Surgery,^** University of Washington, Seattle, Washington; Department of Anatomy with Radiology, The University of Auckland, Auckland, New Zealand

Galactosamine-containing glycosaminoglycans (GAGs), such as the chondroitin sulfate chains of the proteoglycan versican, have been shown to inhibit elastogenesis. Another proteoglycan that may influence elastogenesis is biglycan, which possesses two GAG chains. To assess the importance of these chains on elastogenesis in blood vessels, rat aortic smooth muscle cells were transduced with a GAG-deficient biglycan cDNA-containing retroviral vector (LmBSN). Control cells were transduced with either biglycan or empty vector. Transduced cells were characterized in vitro and then seeded into balloon-injured rat carotid arteries to determine the effects on neointimal structure. Cultured cells overexpressing LmBSN showed marked up-regulation of tropoelastin and fibulin-5 mRNAs, increased amounts of desmosine and insoluble elastin, and increased deposition of elastic fibers as compared with empty vector- and biglycan-transduced cells. Conversely, collagen (1) synthesis and the deposition of collagen fibers were both markedly decreased in LmBSN cultures. In vivo, neointimae formed from cells that overexpressed LmBSN and showed increased deposits of elastin that aggregated into parallel nascent fibers, generally arranged circumferentially. Neointimae that formed from cells with biglycan or empty vector contained fewer and less aggregated deposits of elastin. These findings suggest that the GAG chains of biglycan serve as inhibitors of elastin synthesis and assembly, and that biglycan can act as an important modulator of the composition of the extracellular matrix of blood vessels.