Background: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the blood vessel wall response to hemodynamic forces. We hypothesized that TNF-alpha activity drives neointimal hyperplasia (NIH) during vein graft arterialization and that anti-TNF-alpha therapy would inhibit NIH.
Methods: Rabbits underwent bilateral vein grafting using jugular vein. All distal branches except the occipital artery were unilaterally ligated to create distinct flow environments between the bilateral grafts. Vein grafts were harvested sequentially up to 28 days for TNF-alpha messenger RNA (mRNA) quantitation. In separate experiments, animals received short-term or long-term dosing with pegylated soluble TNF-alpha type I receptor (PEG sTNF-RI) or vehicle. After 14 to 28 days, grafts were analyzed for morphometry, proliferation, apoptosis, and PEG sTNF-RI distribution.
Results: Quantitative mRNA assay (TaqMan) revealed shear-dependent (P < .001) and time-dependent (P < .001) TNF-alpha expression. TNF-alpha induction was maximal at day 1 and gradually decreased over time, but was persistently elevated even 4 weeks later (P < .001). Low shear (associated with increased NIH) resulted in significantly higher TNF-alpha mRNA expression (P = .03). PEG sTNF-RI was found in high concentrations in the serum and localized to NIH. The high-flow and low-flow vein grafts from treated animals demonstrated similar volumes of NIH compared with controls. PEG-sTNF-RI had only modest impact on vascular wall cell turnover, as reflected by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (P = .064) and anti-Ki-67 (P = .12) assays.
Conclusions: Placement of a vein into the arterial circulation acutely upregulates TNF-alpha; this expression level correlates with the degree of subsequent NIH. Pharmacologic interruption of this signaling pathway has no significant impact on NIH or wall cellular proliferation/apoptosis, suggesting that early vein graft adaptations can proceed via TNF-alpha-independent mechanisms.