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Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 16, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn228
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Adrenomedullin induces lymphangiogenesis and ameliorates secondary lymphedema

DongHao Jin1, Kazuhiko Harada2, Shunsuke Ohnishi1, Kenich Yamahara1, Kenji Kangawa2 and Noritoshi Nagaya1,*

1 Department of Regenerative Medicine and Tissue Engineering, and National Cardiovascular Center Research Institute, Osaka, Japan
2 Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan

* Correspondence to: Noritoshi Nagaya Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan Tel: +81-6-6833-5012 Fax: +81-6-6835-5496 E-mail address: nnagaya{at}hotmail.co.jp

Aims: Adrenomedullin (AM) is a multifunctional peptide hormone that plays a significant role in vasodilation and angiogenesis. Lymphedema is a common but refractory disorder that is difficult to treat with conventional therapy. We therefore investigated whether AM promotes lymphangiogenesis and improves lymphedema.

Methods and Results: The effects of AM on lymphatic endothelial cells (LEC) were investigated. AM promoted proliferation, migration and network formation of cultured human lymphatic microvascular endothelial cells (HLMVEC). AM increased intracellular cyclic adenosine monophosphate (cAMP) level in HLMVEC. The cell proliferation induced by AM was inhibited by a cAMP antagonist and mitogen-activated protein kinase kinase (MEK) inhibitors. Phosphorylated extracellular signal-regulated kinase (ERK) in HLMVEC was increased by AM. Continuous administration of AM (0.05 µg/kg/min) to BALB/c mice with tail lymphedema resulted in a decrease in lymphedema thickness. AM treatment increased the number of lymphatic vessels and blood vessels in the injury site.

Conclusions: AM promoted LEC proliferation at least in part through the cAMP/MEK/ERK pathway, and infusion of AM induced lymphangiogenesis and improved lymphedema in mice.

KEYWORDS Adrenomedullin; Lymphangiogenesis; Lymphedema

Time for primary review: 13 days


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