Selective Activation Of Retinoid-X-Receptor (RXR) Activates Proliferation And Migration Of Primary Human Lymphatic Endothelial Cells
Jerry F. Hsu, BS1, Roy P. Yu, BS2, Sun Young Park, MS3, Wan Jiao, MD, PhD2, Dongwon Choi, PhD2, Eun Kyung Park, MS2, Young-Kwon Hong, PhD2, Alex K. Wong, MD3.
1Case Western Reserve University School of Medicine, Cleveland, OH, USA, 2University of Southern California, Keck School of Medicine, Los Angeles, CA, USA, 3City of Hope, Duarte, CA, USA.
PURPOSE: The lymphatic system facilitates interstitial fluid homeostasis while insufficiency triggered by infection or surgery leads to lymphedema. Previously, we showed that 9-cis retinoic acid treatment improves lymphatic regeneration. While we hypothesize that RXR is the critical receptor in lymphatic endothelial cells (LECs) responsible for pro-lymphangiogenic responses, this has not been proven. We show that RXR activation is critical in pro-lymphangiogenic responses in vitro by using bexarotene, an FDA approved 3rd generation retinoid that selectively binds RXR.
METHODS: Human primary lymphatic endothelial cells were treated with DMSO, 9-cis retinoic acid (positive control), or bexarotene in a low serum media (1% FBS) for 48 hours. Proliferation was measured with Cell Proliferation Reagent WST-1 (Roche). Treated cells were seeded as a monolayer in 6-well plates and Matrigel Matrix (Corning) precoated 24-well plates for migration and tube formation assays, respectively.
RESULTS: Compared to DMSO treated controls, LECs treated with 2 μM bexarotene demonstrated an increase in cell number of 145% (p<0.0001). Although a significant increase in rate of migration was not observed in treated LECs compared to controls, bexarotene treatment resulted in increased cord length (p<0.0001), junctions (p<0.001), and meshes (p<0.01) in tube formation assays.
CONCLUSION: Treatment of human lymphatic endothelial cells with bexarotene, a selective RXR agonist, enhances cell proliferation and migration. Future in vivo studies will investigate the effect of bexarotene on lymphangiogenesis and lymphatic vessel regeneration using an experimental mouse tail lymphedema model. As a result, bexarotene could serve as a potential therapeutic agent to treat lymphedema patients.
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