title: Adenoviral transfer of endothelial nitric oxide synthase attenuates lesion formation in a novel murine model of postangioplasty restenosis.
abstract: 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.
  
  
  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+/-0.04x10(5) microm2 to 0.42+/-0.09x10(5) microm2, 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 1.5x10(9) pfu/mL. Ad.APT.eNOS treatment was seen to lead to a 73.1% reduction in plaque size (0.27+/-0.04x10(5) microm2 versus 1.02+/-0.39x10(5) microm2, 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands. thuesen@lacdr.leidenuniv.nl
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: Madelon L
authors.initials: ML
authors.lastname: Fekkes
authors.forename: Robert
authors.initials: R
authors.lastname: Passier
authors.forename: A J
authors.initials: AJ
authors.lastname: van Zonneveld
authors.forename: V
authors.initials: V
authors.lastname: Mainfroid
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000628:therapy; D002342:Carotid Artery, External / Q000201:enzymology / Q000473:pathology / Q000601:surgery / Q000821:virology; D003251:Constriction, Pathologic / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000628:therapy; D023903:Coronary Restenosis / Q000201:enzymology / Q000628:therapy*; D004195:Disease Models, Animal; D004526:Efficiency / Q000502:physiology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology / Q000821:virology; D005260:Female; D005629:Frozen Sections / Q000379:methods; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D007150:Immunohistochemistry; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology / Q000821:virology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D014161:Transduction, Genetic / Q000379:methods / Q000592:standards; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D001616:beta-Galactosidase