Flow-induced neointimal regression in baboon polytetrafluoroethylene grafts is associated with decreased cell proliferation and increased apoptosis

Abstract

Objective: We have previously shown that baboon grafts subjected to elevated shear stress exhibit an increase in luminal area through atrophy of the neointimal layer. This study was designed to investigate the smooth muscle cell (SMC) growth kinetics during early regression and evaluate the influence of nitric oxide (NO) in the regulation of this process.

Methods: Sixteen baboons underwent bilateral polytetrafluorethylene aortoiliac graft placement. After development of a neointima over an 8-week period, blood flow through one graft was increased with placement of a downstream arteriovenous fistula. Grafts were harvested at 4 (n = 6), 7 (n = 5), and 14 (n = 5) days and assessed for neointimal cross-sectional area, SMC proliferation and apoptosis, and macrophage infiltration. High-flow grafts were compared with contralateral normal-flow controls. Eleven baboons underwent an identical experimental preparation to evaluate the effect of NO inhibition. Eight weeks after graft implantation, the animals were treated with an initial bolus (100 mg/kg) followed by continuous infusion (60 mg/kg/d) of either N(G)-nitro-L-arginine methyl ester (L-NAME; n = 6) or the inactive stereoisomer N(G)-nitro-D-arginine methyl ester (n = 5). Grafts were harvested at 7 days and evaluated with the experimental endpoints detailed previously.

Results: Distal fistula placement resulted in a 3.8-fold increase in mean centerline velocity and wall shear stress. Grafts harvested during the initial 14 days after flow manipulation showed a progressive reduction in neointimal cross-sectional area. This change was associated with a decrease in subendothelial SMC proliferation and an increase in neointimal SMC apoptosis, the latter being in the region adjacent to the graft. Animals treated with L-NAME showed a 20% reduction in platelet cyclic guanosine monophosphate and a 17% reduction in serum nitrate/nitrite concentrations. Despite this inhibition of NO production, no effect on the flow-dependent changes in neointimal area, cell proliferation, or apoptosis was observed in the L-NAME-treated baboons.

Conclusion: The local hemodynamic environment within healing prosthetic grafts modulates neointimal SMC proliferation and apoptosis. An increase in graft flow leads to atrophy of the neointima.