Perivascular delivery of a nitric oxide donor inhibits neointimal hyperplasia in vein grafts implanted in the arterial circulation.
OBJECTIVE
Nitric oxide has been reported to reduce intimal hyperplasia as a response to arterial injury. This study was designed to assess the possible effect of perivascular application of a nitric oxide donor on neointimal proliferation occurring in veins exposed to the dynamics of the arterial circulation in a hypercholesterolemic rabbit model.


METHODS
Autologous jugular vein grafts were implanted in the carotid circulation of 20 hypercholesterolemic rabbits. A mixture of a biodegradable polymer and the nitric oxide donor, spermine/nitric oxide, which releases nitric oxide with a half-life of 39 minutes, was applied periadventitially at the time of implantation. Controls were veins bathed in saline solution, polymer alone, and polymer plus the carrier vehicle spermine without nitric oxide. Animals (n = 5 in each group) were put to death on day 28 for morphometric analysis, cell count, and immunohistochemical staining.


RESULTS
Treatment with perivascular nitric oxide donor significantly decreased wall thickness (126 +/- 24 microm vs 208 +/- 45 microm, p = 0.0017) and area (124 +/- 22 microm2/microm vs 211 +/- 37 microm2/microm, p = 0.005). With the carrier vehicle spermine alone, there was a trend toward reduced intimal thickness, but the change was not statistically significant. In the grafts treated with nitric oxide donor, expression of insulin-like growth factor, fibroblast growth factor, thrombospondins, fibronectin, and tenascin was reduced.


CONCLUSIONS
The periadventitial delivery of nitric oxide donor produces a reduction of neointimal hyperplasia in veins implanted in the arterial circulation. The mechanism of action is not entirely clear, but the reduction cannot be explained on the basis of decreased cell proliferation alone. Other possibilities are modulation of protein synthesis of vascular smooth muscle cells and production of extracellular matrix components.
Chaux
A
A
Department of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif, USA.
Ruan
X M
XM
Fishbein
M C
MC
Ouyang
Y
Y
Kaul
S
S
Pass
J A
JA
Matloff
J M
JM
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D002455:Cell Division; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006937:Hypercholesterolemia / Q000473:pathology / Q000601:surgery; D006965:Hyperplasia / Q000517:prevention & control; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D009569:Nitric Oxide / Q000502:physiology*; D011817:Rabbits; D013096:Spermine; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D014656:Vascular Surgical Procedures
D016326:Extracellular Matrix Proteins; D006133:Growth Substances; D013096:Spermine; D009569:Nitric Oxide