© 2000 American Heart Association, Inc.
Integrative Physiology |
Local Expression of Bovine Decorin by Cell-Mediated Gene Transfer Reduces Neointimal Formation After Balloon Injury in Rats
From the Departments of Pathology (J.W.F., M.G.K., S.L., T.N.W.) and Vascular Surgery (J.W.F., M.M.C., A.W.C.), University of Washington, Seattle.
Correspondence to Thomas N. Wight, PhD, Department of Pathology, HSB-Room 507, Box 357470, 1959 NE Pacific St, Seattle, WA 98195-7470. E-mail tnw{at}u.washington.edu
Abstract—Decorin is an extracellular matrix (ECM) proteoglycan that may modify vascular smooth muscle cell (SMC) function by altering the response to growth factors and the accumulation of ECM proteins during vascular injury. To investigate these possibilities in vivo, decorin was overexpressed at the site of arterial injury by cell-mediated gene transfer. Fischer rat SMCs were transduced in vitro with a retroviral construct that contained the bovine decorin gene and were subsequently seeded into injured rat carotid arteries. A species-specific antibody to bovine decorin and polymerase chain reaction primers were used to detect bovine decorin and distinguish it from endogenous rat decorin. Immunohistochemical and Northern analyses of rat carotid arteries revealed only low levels of rat decorin expression up to 8 weeks after balloon injury. However, after cell-mediated transfer of bovine decorin, strong expression of bovine decorin was verified by immunohistochemistry and reverse transcriptase–polymerase chain reaction. Four weeks after injury, the intimal area in vessels seeded with bovine decorin–overexpressing SMCs was significantly reduced by 35±4% (mean±SEM, n=9; P<0.01). Decorin overexpression also induced a higher intimal nuclear density and decreased volume of ECM. Specifically, immunostaining for versican and fibronectin was markedly reduced. In contrast, immunostaining for collagen type I was increased, and electron microscopy confirmed that collagen accumulation was altered. Bromodeoxyuridine labeling indicated that intimal SMC proliferation was not affected by the expression of bovine decorin. In summary, we demonstrate that gene transfer of the ECM proteoglycan, decorin, into the injured arterial wall reduces intimal ECM volume and alters the composition of the ECM.
Key Words: proteoglycans • smooth muscle cells • extracellular matrix • gene therapy • hyperplasia
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