Characterization of an adjustable partial portal vein ligation model reveals flow-dependent intimal and medial remodeling of the extrahepatic portal vein.

Altered portal venous hemodynamics are associated with the development of portosystemic collateralization and structural remodeling of the extrahepatic portal vasculature; however, the underlying cellular and molecular mechanisms remain incompletely understood. Existing partial portal vein ligation models rely on fixed-diameter spacers or needle-based ligation to achieve predefined, non-adjustable levels of portal venous flow restriction, thereby producing discrete levels of hepatic inflow. Consequently, they provide limited control over portal blood flow, intrahepatic perfusion, and the extent of extrahepatic portal vein (EPV) remodeling. Here, we developed a custom adjustable EPV ligation system in mice using a precision threaded bolt and double-nut mechanism calibrated with feeler gauges, enabling controlled and quantifiable EPV diameter reduction and systematic investigation of flow-dependent EPV remodeling. Incremental EPV ligation, ranging from 20% to 80% partial ligation as well as complete ligation, produced graded reductions in portal venous flow and hepatic perfusion as measured by laser Doppler flowmetry. In this study, 50% ligation was selected for cellular and histological analyses because it induced robust and reproducible EPV remodeling characterized by luminal narrowing and coordinated intimal and medial hypertrophy. Vascular remodeling was accompanied by splenomegaly, reduced liver mass, and elevated serum transaminases, consistent with alterations in portal venous system hemodynamics and hepatic consequences associated with reduced portal inflow. Time-course analysis demonstrated progressive intimal thickening from 1 to 3 to 5 weeks after ligation, whereas medial thickening plateaued after 3 weeks, revealing compartment-specific temporal kinetics of vascular remodeling. Quantitative nuclear morphometry demonstrated persistent reductions in nuclear area and perimeter, indicating cellular reprogramming in the ligated EPV. In conclusion, this study establishes a versatile EPV ligation platform enabling graded control of portal venous flow reduction and remodeling severity. This model reveals structured, time-dependent EPV adaptation and identifies extrahepatic vascular and nuclear remodeling as flow-driven features of altered portal venous hemodynamics.