9-Cis Retinoic Acid Promotes Lymphangiogenesis and Enhances Lymphatic Vessel Regeneration Therapeutic Implications of 9-Cis Retinoic Acid for Secondary Lymphedema

• Published in: Circulation (New York, N.Y.) N.Y.), 2012-02, Vol.125 (7), p.872-882
• Main Authors: CHOI, Inho, LEE, Sunju, WEN CHEN, AGUILAR, Berenice, HA NEUL LEE, YOO, Jaehyuk, KOH, Chester J, LU CHEN, WONG, Alex K, HONG, Young-Kwon, HEE KYOUNG CHUNG, YONG SUK LEE, KYU EUI KIM, CHOI, Dongwon, EUN KYUNG PARK, DONGYUN YANG, ECOIFFIER, Tatiana, MONAHAN, John
• Format: Article
• Language: English
• Subjects: Alitretinoin; Animals; Aurora Kinases; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Movement - drug effects; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p57 - genetics; Diseases of the lymphatic vessels; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Endothelial Cells - physiology; Fibroblast Growth Factors - physiology; Lymphangiogenesis - drug effects; Lymphatic Vessels - drug effects; Lymphatic Vessels - physiology; Lymphedema - drug therapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Promoter Regions, Genetic; Protein-Serine-Threonine Kinases - genetics; Regeneration - drug effects; Tretinoin - pharmacology; Tretinoin - therapeutic use
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.111.030296

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. 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. 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.