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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:357.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Adenoviral Transfer of Endothelial Nitric Oxide Synthase Attenuates Lesion Formation in a Novel Murine Model of Postangioplasty Restenosis

Jan H. von der Thüsen; Madelon L. Fekkes; Robert Passier; A.J. van Zonneveld; V. Mainfroid; Theo J.C. van Berkel; Erik A.L. Biessen

From the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (J.H.v.d.T., M.L.F., T.J.C.v.B., E.A.L.B.), Gorlaeus Laboratories, Department of Cardiology, Leiden University Medical Centre (J.H.v.d.T.), and Crucell Holland B.V. (R.P., A.J.v.Z., V.M.), 2333 CN Leiden, The Netherlands.

Correspondence to Jan H. von der Thüsen, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail thuesen{at}lacdr.leidenuniv.nl

Objective— Restenosis remains a major late complication of percutaneous transluminal coronary angioplasty (PTCA), for which the development of prevention strategies has thus far been hampered by the lack of a representative and practical animal model. We have, therefore, developed a murine model of PTCA-induced restenosis.

Methods and Results— Rigid probe angioplasty of pre-existing atherosclerotic lesions in the carotid arteries of ApoE-deficient mice was found to result in an increase in lesion size (0.14±0.04x10⁵ µm² to 0.42±0.09x10⁵ µm², P=0.007) with a smooth muscle cell-rich, fibrotic lesion morphology. In an additional experiment, lesions were incubated immediately after angioplasty with adenovirus bearing an endothelial nitric oxide synthase (eNOS) transgene (Ad.APT.eNOS), or an "empty" control virus (Ad.APT.empty) at a titer of 1.5x10⁹ pfu/mL. Ad.APT.eNOS treatment was seen to lead to a 73.1% reduction in plaque size (0.27±0.04x10⁵ µm² versus 1.02±0.39x10⁵ µm², P=0.07), which translated to a significantly lowered average degree of stenosis (33.6±4.1% versus 74.6±14.0%, P=0.02). Ad.APT.eNOS also decreased lesional collagen content from 29.1% to 4.8% (P<0.001).

Conclusion— We believe that we have established a representative murine model of postangioplasty restenosis, which may serve to elucidate the mechanisms underlying restenosis and to evaluate potential antirestenotic therapies.

Key Words: atherosclerosis • restenosis • mouse model • gene therapy • eNOS

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