Shear Stress-Induced Nitric Oxide Release Triggers the Liver Regeneration Cascade

Abstract

The trigger of the liver regeneration cascade is currently unknown and has been the subject of debate. We hypothesize that, following 2/3 partial hepatectomy (PHX), an increase in the blood flow-to-liver mass ratio results in shear stress-induced nitric oxide (NO) release, which triggers the liver regeneration cascade. Portal venous pressure (PVP), reflecting shear stress in the liver, increased to the same extent following PHX and selective portal vein branch ligation (PVL), a hemodynamic model of PHX, suggesting similar amounts of shear stress in both models. Two indices of the initiation of the liver regeneration cascade were used: proliferative factor (PF) activity in blood 4 h after PHX or PVL and hepatic c-fos mRNA expression 15 min. after PHX or PVL. PF activity and c-fos mRNA expression were increased to similar extents after PHX and PVL, suggesting a similar stimulus in both models. PF activity and c-fos mRNA expression were inhibited by administration of the nitric oxide synthase antagonist, l-NAME, and the NO donor, SIN-1, reversed the inhibition in both models. These results provide support for the hypothesis that a hemodynamic change results in increased shear stress in the liver causing generation of NO, which then triggers the liver regeneration cascade.