Periluminal expression of a secreted transforming growth factor-β type II receptor inhibits in-stent neointima formation following adenovirus-mediated stent-based intracoronary gene transfer.
Transforming growth factor-β1 (TGF-β1) has been shown unequivocally to enhance neointima formation in carotid and ileo-femoral arteries. In our previous studies, however, TGF-β1 expression in coronary arteries actually reduced neointima formation without affecting luminal loss postangioplasty, while expression of a TGF-β1 antagonist (RIIs) in balloon-injured coronary arteries reduced luminal loss without affecting neointima formation. These observed effects may be a consequence of the mode of coronary artery gene transfer employed, but they may also represent differences in the modes of healing of coronary, carotid, and ileo-femoral arteries after endoluminal injury. To help clarify whether a gene therapy strategy to antagonize TGF-β might have application within the coronary vasculature, we have investigated the effect of high-level periluminal expression of RIIs using stent-based adenovirus-mediated intracoronary gene transfer. Porcine coronary arteries were randomized to receive a custom-made CoverStent preloaded with saline only, or with 1×10(9) infectious units of adenovirus expressing RIIs or β-galactosidase (lacZ). Vessels were analyzed 28 days poststenting, at which time angiographic in-stent diameter was significantly greater in RIIs-treated arteries, and in-stent luminal loss significantly reduced. Computerized morphometric minimum in-stent lumen area was ~300% greater in RIIs-exposed vessels than in lacZ or saline-only groups. This was because of significantly reduced neointima formation in the RIIs group. RIIs had no demonstrable effect on cellular proliferation or apoptosis, but greater normalized neointimal/medial collagen content was observed in RIIs-exposed arteries. These data highlight the qualitatively similar effect of TGF-β antagonism on neointima formation in injured coronary and noncoronary arteries, and suggest that since cellular proliferation is unaffected, TGF-β1 antagonism might prevent in-stent restenosis without the delayed healing that is associated with drug-eluting stents in current clinical use.
1 Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, The University of Manchester , Manchester M13 9NT, United Kingdom .
Clare E
CE
Appleby
Parisa
P
Ranjzad
Paul D
PD
Williams
Salik J
SJ
Kakar
Anita
A
Driessen
Edze
E
Tijsma
Brian
B
Fernandes
Anthony M
AM
Heagerty
Paul A
PA
Kingston
D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D017023:Coronary Angiography; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D008907:Mink; D058426:Neointima / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D015607:Stents; D034421:Sus scrofa; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D019076:Transgenes
D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II