VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema.
VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema.
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DOI：
10.1172/jci15830
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发表时间：
2003-03
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影响因子：
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通讯作者：
Y. Yoon;T. Murayama;E. Gravereaux;T. Tkebuchava;Marcy Silver;C. Curry;A. Wecker;R. Kirchmair;C. Hu;M. Kearney;A. Ashare;D. Jackson;H. Kubo;J. Isner;Douglas Losordo
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文献类型：
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作者：
Y. Yoon;T. Murayama;E. Gravereaux;T. Tkebuchava;Marcy Silver;C. Curry;A. Wecker;R. Kirchmair;C. Hu;M. Kearney;A. Ashare;D. Jackson;H. Kubo;J. Isner;Douglas Losordo
虽然水肿是一种常见的临床病症，但对这种致残性病症的治疗仍然有限，并且在很大程度上无效。最近，已经报道VEGF-C的过表达与淋巴管生长（淋巴管生成）增加相关。然而，VEGF-C诱导的淋巴管生成对水肿的影响尚未得到证实。在这里，我们研究了局部转移裸质粒DNA编码的人VEGF-C（phVEGF-C）的两种动物模型的水肿：一个在兔耳和其他在小鼠尾巴的影响。在兔模型中，局部phVEGF-C基因转移后，VEGFR-3表达显著增加。这种基因转移导致水肿的厚度和体积减少，通过连续淋巴管造影证明淋巴功能改善，最后，皮肤的纤维脂肪变化减弱，这是水肿的最终结果。在小鼠尾部模型中再次证实了phVEGF-C对水肿的有利作用。免疫组织化学分析，使用血管特异性标志物：VEGFR-3，淋巴管内皮透明质酸受体-1，以及增殖标志物Ki-67抗体显示，phVEGF-C转染有力地诱导新的淋巴管生长。本研究，我们相信第一次，文件，基因转移phVEGF-C解决水肿通过直接增强淋巴管生成。这种新型治疗策略可能值得对淋巴水肿患者进行临床研究。
Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C-induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was significantly increased. This gene transfer led to a decrease in thickness and volume of lymphedema, improvement of lymphatic function demonstrated by serial lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF-C transfection potently induced new lymphatic vessel growth. This study, we believe for the first time, documents that gene transfer of phVEGF-C resolves lymphedema through direct augmentation of lymphangiogenesis. This novel therapeutic strategy may merit clinical investigation in patients with lymphedema.