9-Cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration therapeutic implications of 9-Cis retinoic acid for secondary lymphedema

Inho Choi, Sunju Lee, Hee Kyoung Chung, Yong Suk Lee, Kyu Eui Kim, Dongwon Choi, Eun Kyung Park, Dongyun Yang, Tatiana Ecoiffier, John Monahan, Wen Chen, Berenice Aguilar, Ha Neul Lee, Jaehyuk Yoo, Chester J. Koh, Lu Chen, Alex K. Wong, Young Kwon Hong

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Background: The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction caused by genetic defects, or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swelling often associated with fibrosis and recurrent infections with no available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema. Methods and Results: We report that RAs promote proliferation, migration, and tube formation of cultured lymphatic endothelial cells by activating fibroblast growth factor receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27 Kip1, p57 Kip2, and the aurora kinases through both an Akt-mediated nongenomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals in mouse trachea, Matrigel plug, and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration. Conclusion: These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients. (Circulation. 2012;125:872-882.)

Original languageEnglish (US)
Pages (from-to)872-882
Number of pages11
JournalCirculation
Volume125
Issue number7
DOIs
StatePublished - Feb 21 2012

Keywords

  • Lymphangiogenesis
  • Lymphatic vessels
  • Lymphedema
  • Receptors
  • Retinoic acid
  • Therapy

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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