From the Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity Institute for Biotechnology (O.V., H.G., R.D.G., P.Z., D.C.,
S.P.J.), and the Cardiac Unit (S.P., N.V., F.V., S.P.J.), KU Leuven, Belgium.
Correspondence to S.P. Janssens, Cardiac Unit and Center for Transgene Technology and Gene Therapy, 49 Herestraat, B-3000 Leuven, Belgium. E-mail stefan.janssens{at}med.kuleuven.ac.be
Background—Nitric oxide, synthesized
from L-arginine by nitric oxide synthase (NOS), is a
vasodilator and inhibits vascular smooth muscle cell (SMC)
proliferation and migration. The effects of local NOS gene
transfer on restenosis after experimental balloon angioplasty
were investigated.
Methods and Results—Left anterior descending coronary
artery angioplasty was performed in 25 pigs. Animals received an
intramural injection of adenovirus (1.5x109 pfu) carrying
either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the
Infiltrator. Local gene transfer efficiency and bioactivity of
recombinant protein were assessed after 4 days. Indices of
restenosis were evaluated by computerized planimetry on
coronary artery sections prepared 28 days after angioplasty.
Adenoviral vectors permitted efficient gene delivery to medial SMCs and
adventitial cells of coronary arteries. Vascular cGMP levels
were depressed after angioplasty from 1.30±0.42 to 0.33±0.20 pmol/mg
protein (P<0.05) but were restored after constitutive
endothelial (ce) NOS gene transfer to
1.82±0.98 pmol/mg (P<0.05 versus injured group and
P=NS versus control). The ratio of the
neointimal area to the internal elastic lamina fracture
length, maximal neointimal thickness, and percent
stenosis were all reduced in AdCMVceNOS- versus
AdRR5-transduced pigs (0.59±0.14 versus 0.80±0.19 mm,
P=0.02; 0.75±0.21 versus 1.04±0.25 mm,
P=0.019; and 53±15% versus 75±11%,
P=0.006, respectively). Lumen area was significantly
larger (0.70±0.35 mm2 in AdCMVceNOS versus
0.32±0.18 mm2 in AdRR5, P=0.007).
Conclusions—Percutaneous adenovirus-mediated
NOS gene transfer resulted in efficient local overexpression
of functional NOS after angioplasty in
coronary arteries. Restored NO production in injured
coronary arteries significantly reduced luminal narrowing, most
likely through a combined effect on neointima formation and
on vessel remodeling after angioplasty.
© 1998 American Heart Association, Inc.
Basic Science Reports
Local Adenovirus-Mediated Transfer of Human Endothelial Nitric Oxide Synthase Reduces Luminal Narrowing After Coronary Angioplasty in Pigs
Key Words: genes • vessels • remodeling • restenosis • nitric oxide
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