An Important Role of VEGF-C in Promoting Lymphedema Development.

Gousopoulos, Epameinondas; Proulx, Steven T; Bachmann, Samia B; Dieterich, Lothar C; Scholl, Jeannette; Karaman, Sinem; Bianchi, Roberta; Detmar, Michael (2017). An Important Role of VEGF-C in Promoting Lymphedema Development. Journal of investigative dermatology, 137(9), pp. 1995-2004. Elsevier 10.1016/j.jid.2017.04.033

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Secondary lymphedema is a common complication after cancer treatment, but the pathomechanisms underlying the disease remain unclear. Using a mouse tail lymphedema model, we found an increase in local and systemic levels of the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C and identified CD68+ macrophages as a cellular source. Surprisingly, overexpression of VEGF-C in a transgenic mouse model led to aggravation of lymphedema with increased immune cell infiltration and vascular leakage compared with wild-type littermates. Conversely, blockage of VEGF-C by overexpression of soluble VEGF receptor-3 reduced edema development, diminishing inflammation and blood vascular leakage. Similar findings were obtained in a hind limb lymph node excision lymphedema model. Flow cytometry analyses and immunofluorescence stainings in lymphedematic tissue showed that VEGF receptor-3 expression was restricted to lymphatic endothelial cells. Our data suggest that endogenous VEGF-C causes blood vascular leakage and fluid influx into the tissue, thus actively contributing to edema formation. These data may provide the basis for future clinical therapeutic approaches.

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