title: 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Southern California, Norris Comprehensive Cancer Center, 1450 Biggy St, NRT6501, Los Angeles, CA 90033, USA.
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
authors.forename: Sunju
authors.initials: S
authors.lastname: Lee
authors.forename: Hee
authors.initials: H
authors.lastname: Kyoung Chung
authors.forename: Yong
authors.initials: Y
authors.lastname: Suk Lee
authors.forename: Kyu
authors.initials: K
authors.lastname: Eui Kim
authors.forename: Dongwon
authors.initials: D
authors.lastname: Choi
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Park
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ecoiffier
authors.forename: John
authors.initials: J
authors.lastname: Monahan
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Berenice
authors.initials: B
authors.lastname: Aguilar
authors.forename: Ha Neul
authors.initials: HN
authors.lastname: Lee
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Yoo
authors.forename: Chester J
authors.initials: CJ
authors.lastname: Koh
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: Alex K
authors.initials: AK
authors.lastname: Wong
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D064127:Aurora Kinases; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000502:physiology; D042583:Lymphangiogenesis / Q000187:drug effects*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000502:physiology*; D008209:Lymphedema / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012038:Regeneration / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C493961:Cdkn1b protein, mouse; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077556:Alitretinoin; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases