Published Online
on September 4, 2006

A more recent version of this article appeared on September 12, 2006

This Article Full Text (PDF) All Versions of this Article: 114/11/1177    most recent CIRCULATIONAHA.105.602953v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saito, Y. Articles by Kaneda, Y. Search for Related Content PubMed PubMed Citation Articles by Saito, Y. Articles by Kaneda, Y. Related Collections Angiogenesis Growth factors/cytokines

Submitted on November 22, 2005
Revised on June 19, 2006
Accepted on July 14, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: nakagami{at}gts.med.osaka-u.ac.jp.

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.

Key words: gene therapy • hepatocyte growth factor • lymphangiogenesis

This article has been cited by other articles:

				M. Mori, H. Nakagami, N. Koibuchi, K. Miura, Y. Takami, H. Koriyama, H. Hayashi, H. Sabe, N. Mochizuki, R. Morishita, et al. Zyxin Mediates Actin Fiber Reorganization in Epithelial-Mesenchymal Transition and Contributes to Endocardial Morphogenesis Mol. Biol. Cell, July 1, 2009; 20(13): 3115 - 3124. [Abstract] [Full Text] [PDF]

				W. P. Dunworth and K. M. Caron G Protein-Coupled Receptors as Potential Drug Targets for Lymphangiogenesis and Lymphatic Vascular Diseases Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 650 - 656. [Abstract] [Full Text] [PDF]

				D. Jin, K. Harada, S. Ohnishi, K. Yamahara, K. Kangawa, and N. Nagaya Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphoedema Cardiovasc Res, December 1, 2008; 80(3): 339 - 345. [Abstract] [Full Text] [PDF]

				S. G. Rockson Diagnosis and Management of Lymphatic Vascular Disease J. Am. Coll. Cardiol., September 2, 2008; 52(10): 799 - 806. [Abstract] [Full Text] [PDF]

				C. Hadamitzky and R. Pabst Acquired Lymphedema: An Urgent Need for Adequate Animal Models Cancer Res., January 15, 2008; 68(2): 343 - 345. [Abstract] [Full Text] [PDF]