Transfection of Human Hepatocyte Growth Factor Gene Ameliorates Secondary Lymphedema via Promotion of Lymphangiogenesis
Transfection of Human Hepatocyte Growth Factor Gene Ameliorates Secondary Lymphedema via Promotion of Lymphangiogenesis
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DOI：
10.1161/circulationaha.105.602953
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发表时间：
2006-09
期刊：
影响因子：
37.8
通讯作者：
Yukihiro Saito;H. Nakagami;R. Morishita;Y. Takami;Y. Kikuchi;H. Hayashi;T. Nishikawa;K. Tamai;N. Azuma;T. Sasajima;Y. Kaneda
中科院分区：
文献类型：
--
作者：
Yukihiro Saito;H. Nakagami;R. Morishita;Y. Takami;Y. Kikuchi;H. Hayashi;T. Nishikawa;K. Tamai;N. Azuma;T. Sasajima;Y. Kaneda
背景-淋巴水肿是一种淋巴血管系统的紊乱，以淋巴回流受损和肢体肿胀为特征。对这种致残情况的治疗仍然有限，而且基本上无效。本研究旨在探讨肝细胞生长因子(HGF)对淋巴水肿动物模型的治疗效果。方法和结果-免疫荧光分析显示，犬原代淋巴管内皮细胞(CLECs)淋巴管特异性标志物(血管内皮生长因子受体-3、Lyve-1、泊多普宁和Prox1)和HGF受体c-Met呈阳性。重组人肝细胞生长因子作用于CLECs后，细胞的生长和迁移呈剂量依赖性增加，细胞外信号调节激酶和Akt活性增强。在人晶状体上皮细胞中，c-Met也有表达，HGF以剂量依赖的方式促进细胞的生长和迁移。在CLECs中转染人HGF质粒DNA也能提高c-fos启动子的活性。此外，每周一次的HGF基因转移通过破坏淋巴管导致大鼠尾部淋巴水肿模型，导致淋巴水肿厚度减少。尽管HGF和血管内皮生长因子165注射组内皮细胞标记物PECAM-1的表达均增加，但LEC标记物(LYVE-1和Prox1)的表达仅在HGF注射组增加。结论--这些数据表明，通过质粒转移表达HGF可以通过促进淋巴管生成来改善淋巴水肿。进一步研究以确定这一方法的临床实用性将对淋巴水肿患者有利。
Background— Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return and swelling of the extremities. Treatment for this disabling condition remains limited and largely ineffective. The goal of the present study was to investigate the therapeutic efficacy of hepatocyte growth factor (HGF) in animal models of lymphedema. Methods and Results— Immunofluorescent analysis demonstrated that canine primary lymphatic endothelial cells (cLECs) were positive for lymphatic-specific markers (vascular endothelial growth factor receptor-3, LYVE-1, podoplanin, and Prox1) and the HGF receptor c-Met. Treating cLECs with human recombinant HGF resulted in a dose-dependent increase in cell growth and migration and increased activity of extracellular signal-regulated kinase and Akt. In human LECs, c-Met also was expressed, and treatment with HGF increased cell growth and migration in a dose-dependent manner. Transfection of human HGF plasmid DNA in cLECs also increased the c-fos promoter activity. Furthermore, weekly HGF gene transfer in a rat tail lymphedema model by disruption of lymphatic vessels resulted in a decrease in lymphedema thickness. Although expression of the endothelial cell marker PECAM-1 was increased in both HGF- and vascular endothelial growth factor 165–injected groups, expression of LEC markers (LYVE-1 and Prox1) was increased only in the HGF-injected group. Conclusions— These data demonstrate that expression of HGF via plasmid transfer improves lymphedema via promotion of lymphangiogenesis. Further studies to determine the clinical utility of this approach would be of benefit to patients with lymphedema.