An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis

Evaluation of the efficacy of molecular treatment strategies for lymphatic vascular insufficiency requires a suitable preclinical animal model. Ideally, the model should closely replicate the untreated human disease in its pathogenesis and pathological expression. We have undertaken a study of the time course of the development and resolution of acquired, experimental lymphedema and of its responses to vascular endothelial growth factor (VEGF)-C lymphangiogenesis in the mouse tail model. We provoked post-surgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C. Quantitative assessment of immune traffic function was performed through sequential in vivo bioluminescent imaging. In untreated lymphedema, tail edema was sustained until day 21. Exogenous administration of human recombinant VEGF-C produced a significant decrease in volume. Untreated lymphedema in the mouse tail model was characterized by the presence of dilated cutaneous lymphatics, marked acute inflammatory changes, and hypercellularity; VEGF-C produced a substantial reversion to the normal pattern, with notable regression in the size and number of cutaneous lymphatic vessels that express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). In vivo imaging confirmed the presence of an impairment of immune traffic in lymphedema that was ameliorated after VEGF-C administration. The post-surgical murine tail model of lymphedema closely simulates attributes of human lymphedema and provides the requisite sensitivity to detect therapeutically induced functional and structural alterations. It can, therefore, be used as an investigative platform to assess mechanisms of disease and its responses to candidate therapies, such as therapeutic lymphangiogenesis.