Adenovirus-mediated gene transfer of transforming growth factor-beta3, but not transforming growth factor-beta1, inhibits constrictive remodeling and reduces luminal loss after coronary angioplasty.
BACKGROUND
Extracellular matrix (ECM) remodeling is central to the development of restenosis after PTCA. Substantial evidence implicates transforming growth factor-beta1 (TGF-beta1), a regulator of ECM deposition by vascular cells, in its pathogenesis. TGF-beta3 reduces TGF-beta1-induced ECM deposition in cutaneous wounds. We therefore investigated the effects of intracoronary expression of TGF-beta3 and TGF-beta1 on luminal loss after angioplasty.


RESULTS
Porcine coronary arteries received an adenovirus expressing TGF-beta3, TGF-beta1, or lacZ (beta-galactosidase), or PBS only, at the site of angioplasty. Morphometric analysis 28 days after angioplasty confirmed reduced luminal loss in TGF-beta3 vessels (-0.65+/-0.10 mm2) compared with lacZ (-1.18+/-0.19 mm2) or PBS only (-1.19+/-0.17 mm2; P=0.003). Luminal loss was not reduced in TGF-beta1 vessels (-1.02+/-0.19 mm2; P=0.48). An increase in the external elastic lamina area in TGF-beta3-treated vessels (+0.73+/-0.32 mm2) contrasted with decreases in control vessels (mean, -0.53+/-0.17 mm2; P=0.001) and TGF-beta1 vessels (-0.87+/-0.34 mm2; P=0.003). Collagen content increased at the site of injury in TGF-beta3-treated vessels (26.1+/-14.2%) but decreased in the lacZ (-22.8+/-6.6%) and PBS-only (-23.4+/-7.0%; P=0.002) groups and was not significantly changed in TGF-beta1-treated vessels.


CONCLUSIONS
Expression of TGF-beta3 inhibits constrictive remodeling after PTCA and reduces luminal loss. This is accompanied by increased adventitial collagen, which may act as an external "scaffold" preventing vessel constriction. These findings confirm the potential of gene therapies that modify ECM remodeling for prophylaxis of restenosis.
Kingston
Paul A
PA
Vascular Gene Therapy Unit, University of Manchester, Manchester, UK. paul.a.kingston@man.ac.uk
Sinha
Sanjay
S
Appleby
Clare E
CE
David
Anne
A
Verakis
Thomas
T
Castro
Maria G
MG
Lowenstein
Pedro R
PR
Heagerty
Anthony M
AM
D000256:Adenoviridae / Q000235:genetics*; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D008907:Mink; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D019076:Transgenes; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D003094:Collagen