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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 24; no. 2; pp. 357 - 362
• Main Authors: von der Thüsen, Jan H, Fekkes, Madelon L, Passier, Robert, van Zonneveld, A.J, Mainfroid, V, van Berkel, Theo J.C, Biessen, Erik A.L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2004; Hagerstown, MD Lippincott
• Subjects: Adenoviridae - genetics; Angioplasty, Balloon, Coronary - adverse effects; Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis (general aspects, experimental research); beta-Galactosidase - analysis; beta-Galactosidase - biosynthesis; beta-Galactosidase - genetics; beta-Galactosidase - immunology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Artery Diseases - enzymology; Carotid Artery Diseases - etiology; Carotid Artery Diseases - pathology; Carotid Artery Diseases - therapy; Carotid Artery, External - enzymology; Carotid Artery, External - pathology; Carotid Artery, External - surgery; Carotid Artery, External - virology; Constriction, Pathologic - enzymology; Constriction, Pathologic - etiology; Constriction, Pathologic - pathology; Constriction, Pathologic - therapy; Coronary Restenosis - enzymology; Coronary Restenosis - therapy; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Efficiency - physiology; Endothelium, Vascular - enzymology; Endothelium, Vascular - pathology; Endothelium, Vascular - virology; Female; Frozen Sections - methods; Genetic Therapy; Genetic Vectors - biosynthesis; Genetic Vectors - genetics; Genetic Vectors - therapeutic use; Immunohistochemistry; Medical sciences; Mice; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - virology; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - therapeutic use; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Transduction, Genetic - methods; Transduction, Genetic - standards; eNOS; mouse model; Enzyme; Rodentia; Cardiovascular disease; Nitric-oxide synthase; Vascular disease; Restenosis; Vertebrata; Mammalia; Treatment; Mouse; Animal; Atherosclerosis; Oxidoreductases; Gene therapy
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000114235.51044.92

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±0.04×10 μm to 0.42±0.09×10 μm, 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 1.5×10 pfu/mL. Ad.APT.eNOS treatment was seen to lead to a 73.1% reduction in plaque size (0.27±0.04×10 μm versus 1.02±0.39×10 μm, 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.