title: Adenovirus-mediated gene transfer of a secreted transforming growth factor-beta type II receptor inhibits luminal loss and constrictive remodeling after coronary angioplasty and enhances adventitial collagen deposition.
abstract: BACKGROUND
  Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-beta1 on luminal loss after PTCA.
  
  
  RESULTS
  Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-beta type II receptor (Ad5-RIIs), an adenovirus expressing beta-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs-injected arteries (1.71+/-0.12 mm(2)) than in the Ad5-lacZ (1.33+/-0.13 mm(2)) or vehicle-only (1.08+/-0.17 mm(2); P=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (P=0.013) and external (P=0.031) elastic laminae in Ad5-RIIs-treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (P=0.004).
  
  
  CONCLUSIONS
  Adenovirus-mediated antagonism of TGF-beta1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-beta1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy-mediated antagonism of TGF-beta1 as prophylactic therapy for restenosis.
authors.affiliation: Molecular Medicine and Gene Therapy Unit, University of Manchester, Department of Medicine, Manchester Royal Infirmary, Manchester, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Kingston
authors.forename: S
authors.initials: S
authors.lastname: Sinha
authors.forename: A
authors.initials: A
authors.lastname: David
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
authors.forename: P R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: A M
authors.initials: AM
authors.lastname: Heagerty
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D003251:Constriction, Pathologic / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D023903:Coronary Restenosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors; D007249:Inflammation / Q000209:etiology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000096:biosynthesis; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D013552:Swine; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D001616:beta-Galactosidase