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(Circulation Research. 2006;98:370.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Inhibition of Versican Synthesis by Antisense Alters Smooth Muscle Cell Phenotype and Induces Elastic Fiber Formation In Vitro and in Neointima After Vessel Injury

Robert Huang, Mervyn J. Merrilees, Kathleen Braun, Brent Beaumont, Joan Lemire, Alexander W. Clowes, Aleksander Hinek, Thomas N. Wight

From the Department of Anatomy with Radiology (R.H., M.J.M., B.B.), The University of Auckland, New Zealand; Hope Heart Program at Benaroya Research Institute at Virginia Mason (K.B., T.N.W.), Seattle, Wash; Department of Anatomy and Cell Biology (J.L.), Tufts University School of Medicine, Boston, Mass; Department of Surgery (A.W.C.), University of Washington, Seattle; and The Hospital for Sick Children (A.H.), Toronto, Canada.

Correspondence to Prof Mervyn J. Merilees, Department of Anatomy with Radiology, The University of Aukland, Private Bag 92019, Auckland, New Zealand. E-mail m.merrilees{at}auckland.ac.nz

The proteoglycan versican is implicated in several atherogenic events, including stimulation of vascular smooth muscle cell (VSMC) growth and migration, retention of lipoproteins, and promotion of thrombogenesis. A high content of intimal versican also correlates with a low content of elastin, suggesting an inhibitory role for versican in elastogenesis. To determine whether reduced production of versican can be used to enhance elastogenesis, we transduced Fischer rat VSMC (FRSMC) with a versican antisense sequence using the retroviral vector LXSN. Stable expression of versican antisense (LVaSN) significantly reduced versican production, induced a flattened morphology, reduced cell proliferation and migration, increased tropoelastin synthesis, increased elastin binding protein (S-Gal/EBP), and increased deposition of elastic fibers in long-term cultures. Add-back of chondroitin sulfate chains, or versican, decreased S-Gal/EBP and elastic fiber formation. LVaSN cells seeded into balloon catheter-injured rat carotid arteries formed neointimae containing low levels versican, increased amounts of S-Gal/EBP, and increased elastin deposits 7 days postinjury. At 4 weeks, neointimae formed from LVaSN cells were highly structured and contained multiple layers of elastic fibers and lamellae. These results indicate a central role for versican and its constituent chondroitin sulfate chains in controlling cell phenotype, elastogenesis, and intimal structure.

Key Words: versican antisense • elastogenesis • vascular injury • remodeling