Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland.
J Invest Dermatol. 2017 Sep;137(9):1995-2004. doi: 10.1016/j.jid.2017.04.033. Epub 2017 May 17.
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.
继发性淋巴水肿是癌症治疗后的常见并发症，但该病的发病机制仍不清楚。我们使用小鼠尾巴淋巴水肿模型发现，局部和全身的淋巴管生成因子血管内皮生长因子（VEGF）-C 水平升高，并鉴定出 CD68 巨噬细胞是其细胞来源。令人惊讶的是，与野生型同窝仔相比，VEGF-C 在转基因小鼠模型中的过表达导致淋巴水肿加重，免疫细胞浸润和血管渗漏增加。相反，通过过表达可溶性 VEGF 受体-3 阻断 VEGF-C 减少了水肿的发展，减轻了炎症和血管渗漏。在后肢淋巴结切除淋巴水肿模型中也得到了类似的发现。在淋巴水肿组织中的流式细胞术分析和免疫荧光染色表明，VEGF 受体-3 表达仅限于淋巴管内皮细胞。我们的数据表明，内源性 VEGF-C 导致血管渗漏和液体涌入组织，从而积极促进水肿形成。这些数据可能为未来的临床治疗方法提供基础。
