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(Circulation. 2006;114:1177-1184.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Transfection of Human Hepatocyte Growth Factor Gene Ameliorates Secondary Lymphedema via Promotion of Lymphangiogenesis

Yukihiro Saito, MD; Hironori Nakagami, MD, PhD; Ryuichi Morishita, MD, PhD; Yoichi Takami, MD; Yasushi Kikuchi, MD, PhD; Hiroki Hayashi, BS; Tomoyuki Nishikawa, PhD; Katsuto Tamai, MD, PhD; Nobuyoshi Azuma, MD, PhD; Tadahiro Sasajima, MD, PhD; Yasufumi Kaneda, MD, PhD

From the Divisions of Gene Therapy Science (Y.S., H.N., Y.T., Y.K., H.H., T.N., K.T., Y.K.) and Clinical Gene Therapy (R.M.), Graduate School of Medicine, Osaka University, Osaka, and Department of Surgery, Asahikawa Medical University, Hokkaido (Y.S., N.A., T.S.), Japan.

Correspondence to Hironori Nakagami, MD, PhD, Assistant Professor, Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail nakagami{at}gts.med.osaka-u.ac.jp

Received November 22, 2005; revision received June 19, 2006; accepted July 14, 2006.

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.

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