DOI: 10.1097/js9.0000000000005616 ISSN: 1743-9159
Time-dependent mechanisms of growth and remodeling in the lymphatics in a sheep model of lymphatic injury
Young Jae Ryu, Zhanna Nepiyushchikh, Sophia Mavris, Shao-Yun Hsu, Rudolph L. Gleason, J. Brandon Dixon
Background:
Injury to lymphatic vessels, such as during cancer surgery, impairs lymph flow and progressively leads to lymphedema. While rodent lymphedema models have advanced understanding of molecular and cellular mechanisms, they do not replicate the hydrostatic pressures or chronic remodeling features observed in humans. Large-animal models, such as sheep, provide a more physiologically relevant platform for studying lymphatic growth and remodeling (G&R). However, studies have not simultaneously tracked the temporal evolution of lymphatic vessel tissue mechanics
ex vivo
while juxtaposing these changes with
in vivo
functional metrics measured at the same post-injury time points. We aimed to establish the first temporal framework of lymphatic G&R in a sheep model of vessel ligation, directly linking
in vivo
transport dynamics with
ex vivo
functional and structural adaptation.
Methods:
Twelve sheep underwent popliteal lymphatic vessel ligation to simulate injury and were studied at 2, 4, or 8 weeks post-surgery. Near-infrared imaging quantified
in vivo
pump function before surgery and at each endpoint. At study termination, vessels were excised for
ex vivo
functional, structural, and mechanical testing under varying pressure-loading conditions. Pressure-dependent responses were analyzed using nonlinear mixed-effects modeling.
Results:
In vivo
, packet transport was significantly increased in remodeled vessels at 8 weeks, reflecting enhanced lymph propulsion.
Ex vivo
, remodeled vessels exhibited progressive enlargement of diameter while maintaining wall thickness. Functional remodeling followed a biphasic trajectory: early elevations in tone, ejection fraction, and mechanical work at 2 weeks; transient attenuation with reduced compliance at 4 weeks; and reinforced pumping capacity at 8 weeks.
Conclusion:
This study provides the first longitudinal, multi-timepoint characterization of lymphatic vessel growth and remodeling in response to mechanical injury under gravity-influenced conditions, revealing stage-specific functional adaptations that link
in vivo
lymphatic behavior to the progression of remodeling. These findings establish experimental grounding for time-dependent computational models and suggest that effective lymphedema therapies may require stage-specific modulation of lymphatic function, with important implications for understanding human lymphedema progression.