Background-Pathological vascular remodeling in venous bypass grafts (VGs) r
esults in smooth muscle cell (SMC) intimal hyperplasia and provides the sub
strate for progressive atherosclerosis, the principal cause of late VG fail
ure. Nitric oxide (NO) bioactivity is reduced in VGs, in association with i
ncreased vascular superoxide production, but how these features relate to p
athological VG remodeling remains unclear. We used gene transfer of the neu
ronal isoform of nitric oxide synthase (nNOS) to investigate how increased
NO production modulates vascular remodeling in VGs and determined the effec
ts on late VG phenotype.
Methods and Results-New Zealand White rabbits (n=60) underwent jugular-caro
tid interposition bypass graft surgery with intraoperative adenoviral gene
transfer of nNOS or beta -galactosidase. Vessels were analyzed after 3 days
(early, to investigate acute injury/inflammation) or 28 days (late, to inv
estigate SMC intimal hyperplasia). In early VGs, nNOS gene transfer signifi
cantly increased NOS activity and substantially reduced adhesion molecule e
xpression and inflammatory cell infiltration. In late VGs, recombinant nNOS
protein was no longer evident, but there were sustained effects on VG remo
deling, resulting in a striking reduction in SMC intimal hyperplasia, a mor
e differentiated intimal SMC phenotype, and reduced vascular superoxide pro
duction.
Conclusions-Intraoperative nNOS gene transfer has sustained favorable effec
ts on VG remodeling and on the vascular phenotype of mature VGs. These find
ings suggest that early, transient modification of the response to vascular
injury is a powerful approach to modulate VG biology and highlight the pot
ential utility of NOS gene transfer as a therapeutic strategy in VGs.