TNF-alpha and shear stress-induced large artery adaptations

Tumor necrosis factor-alpha (TNF-alpha) up-regulation has been associated with both low and high shear-induced arterial remodeling. To address this apparent paradox and to define the biology of TNF-alpha signaling in large arteries, we tested the hypotheses that differential temporal expression of TNF-alpha drives shear-regulated arterial remodeling.

Both low- and high-shear environments in the same rabbit were surgically created for common carotid arteries. Common carotid arteries (n = 60 total) were harvested after d0, d1, d3, d7, and d14 and analyses included morphology, TNF-alpha, and IL-10 mRNA quantitation. In separate experiments, animals received pegylated soluble TNF-alpha Type 1 receptor (PEG sTNF-RI) or vehicle via either short- or long-term dosing to define the effect of TNF-alpha blockade.

The model yielded a 14-fold shear differential (P < 0.001) with medial thickening under low shear (P = 0.025), and evidence of outward remodeling with high shear (P = 0.007). Low shear immediately up-regulated TNF-alpha expression approximately 50 fold (P < 0.001) at d1. Conversely, high shear-induced delayed and sustained TNF-alpha expression (22-fold at d7, P = 0.012; 23-fold at d14, P = 0.007). Both low and high shear gradually induced IL-10 expression (P = 0.002 and P = 0.004, respectively). Neither short-term (5-day) nor long-term (14-day) blockage of TNF-alpha signaling resulted in treatment-induced changes in the remodeling of low- or high-shear arteries.

Shear stress differentially and temporally regulates TNF-alpha expression in remodeling large arteries. However, TNF-alpha blockage did not substantially impact the final shear-induced morphology, suggesting that large arteries can remodel in response to flow perturbations independent of TNF-alpha signaling.