Nitric oxide synthase (nNOS) gene transfer modifies venous bypass graft remodeling - Effects on vascular smooth muscle cell differentiation and superoxide production

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.