Wall shear modulation of cytokines in early vein grafts

Abstract

Objective: Pro-inflammatory cytokine-driven mechanisms have been implicated in vein graft failure, though little is known about the effect of hemodynamic factors and anti-inflammatory counter-regulatory mechanisms. We hypothesized that early temporal expression of the pro-inflammatory cytokine interleukin (IL)-1 beta and the anti-inflammatory cytokine IL-10 proceeds by way of wall shear stress-dependent pathways in the arterializing vein graft.

Methods: Rabbits (n = 27) underwent bilateral jugular vein carotid interposition grafts, and simultaneous unilateral distal carotid branch ligation, to produce both low-flow and high-flow grafts in the same animal. Vein grafts were harvested at 1, 3, 7, 14, and 28 days and were assessed for architecture, wall shear stress, and cytokine messenger RNA levels (quantitative real-time two-step reverse transcription polymerase chain reaction).

Results: The model resulted in an immediate 90% flow reduction (P <.001, paired t test) in the vein graft on the ligated side, and a 36% increase (P =.01) in contralateral graft flow. This persisted as approximately 15-fold flow differential throughout the 28-day period. The construction yielded a 15-fold differential in wall shear stress between low-flow and high-flow vein grafts (P <.001, two-way repeated measures analysis of variance). Intimal hyperplasia began by day 3, and was 6-fold more in low wall shear grafts by 28 days (230.6 +/- 35.4 microm intimal thickness vs 36.1 +/- 17.6 microm for low shear versus high shear grafts; P =.001). For both cytokines time independently affected mRNA expression (P <.001, global analysis of variance). Exposure of vein grafts to the arterial circulation markedly up-regulated IL-1 beta at 1 day, with significantly more induction in the low shear setting (P =.002). IL-1 beta protein localized to the developing neointima at days 1 and 3. Conversely, IL-10 slowly increased until day 14, with significantly more expression in the high shear grafts (P <.001).

Conclusions: Vein graft adaptation induces early pro-inflammatory cytokine IL-1 beta expression and delayed protective IL-10 expression (most notable under high shear conditions), both of which are modulated by wall shear. These differential temporal windows offer strategies for appropriately timed pro-inflammatory or anti-inflammatory therapies to interrupt pathologic vein graft adaptations.

Clinical relevance: Neointimal hyperplasia continues to limit the durability of vein bypass grafts. Emerging evidence suggests that inflammatory mechanisms drive the neointimal hyperplasic response. This study demonstrates that specific hemodynamic forces (altered wall shear stress) differentially affect early pro-inflammatory interleukin (IL)-1 beta and delayed anti-inflammatory IL-10 signaling. These distinct temporal windows for IL-1 beta and IL-10 cytokine expression offer strategies for appropriately timed pro-inflammatory and anti-inflammatory therapies to interrupt pathologic vein graft adaptations.