Lymphatic Vasculature Requires Estrogen Receptor- Signaling to Protect From Lymphedema

Abstract : Objective Estrogens exert beneficial effect on the blood vascular system. However, their role on the lymphatic system has been poorly investigated. We studied the protective effect of the 17 estradiolthe most potent endogenous estrogenin lymphedemaa lymphatic dysfunction, which results in a massive fluid and fat accumulation in the limb. Approach and Results Screening of DNA motifs able to mobilize ERs (estrogen receptors) and quantitative real-time polymerase chain reaction analysis revealed that estradiol promotes transcriptional activation of lymphangiogenesis-related gene expression including VEGF (vascular endothelial growth factor)-D, VEGFR (VEGF receptor)-3, lyve-1, and HASs (hyaluronan synthases). Using an original model of secondary lymphedema, we observed a protective effect of estradiol on lymphedema by reducing dermal backflowa representative feature of the pathology. Blocking ER by tamoxifenthe selective estrogen modulatorled to a remodeling of the lymphatic network associated with a strong lymphatic leakage. Moreover, the protection of lymphedema by estradiol treatment was abrogated by the endothelial deletion of the receptor ER in Tie2-Cre; ERlox/lox mice, which exhibit dilated lymphatic vessels. This remodeling correlated with a decrease in lymphangiogenic gene expression. In vitro, blocking ER by tamoxifen in lymphatic endothelial cells decreased cell-cell junctions, inhibited migration and sprouting, and resulted in an inhibition of Erk but not of Akt phosphorylation. Conclusions Estradiol protection from developing lymphedema is mediated by an activation of its receptor ER and is antagonized by tamoxifen. These findings reveal a new facet of the estrogen influence in the management of the lymphatic system and provide more evidence that secondary lymphedema is worsened by hormone therapy.
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Submitted on : Tuesday, August 28, 2018 - 11:15:50 AM
Last modification on : Wednesday, October 30, 2019 - 3:24:02 PM

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Florent Morfoisse, Florence Tatin, Benoit Chaput, Nicole Therville, Charlotte Vaysse, et al.. Lymphatic Vasculature Requires Estrogen Receptor- Signaling to Protect From Lymphedema. Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2018, 38 (6), pp.1346-1357. ⟨10.1161/ATVBAHA.118.310997⟩. ⟨hal-01863214⟩

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