Tumor necrosis factor-α and the early vein graft

BackgroundTumor necrosis factor-α (TNF-α) has been implicated in the blood vessel wall response to hemodynamic forces. We hypothesized that TNF-α activity drives neointimal hyperplasia (NIH) during vein graft arterialization and that anti-TNF-α therapy would inhibit NIH.MethodsRabbits 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-α messenger RNA (mRNA) quantitation. In separate experiments, animals received short-term or long-term dosing with pegylated soluble TNF-α 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.ResultsQuantitative mRNA assay (TaqMan) revealed shear-dependent (P < .001) and time-dependent (P < .001) TNF-α expression. TNF-α 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-α 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.ConclusionsPlacement of a vein into the arterial circulation acutely upregulates TNF-α; 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-α–independent mechanisms.

Clinical RelevanceNeointimal hyperplasia stands as a fundamental pathology of vein graft failure. This study reveals that low wall shear significantly upregulates early and acute proinflammatory cytokine tumor necrosis factor-α (TNF-α) in vein grafts (with robust neointimal formation), whereas high wall shear is associated with less TNF-α induction and neointimal hyperplasia. Further studies demonstrate that blockage of inflammatory TNF-α signaling fails to abrogate occlusive vein graft lesions. Thus, further research is required to delineate the biologic significance of the TNF-α expression dynamics observed in the early vein graft.