Florent Morfoisse1, Florence Tatin1, Benoit Chaput2, Nicole Therville3, Charlotte Vaysse4, Raphael Métivier5, Julie Malloizel-Delaunay6, Francoise Pujol1, Anne-Claire Godet1, Fabienne De Toni1, Frederic Boudou1, Katia Grenier7, David Dubuc7, Eric Lacazette1, Anne-Catherine Prats1, Julie Guillermet-Guibert3, Francoise Lenfant1, Barbara Garmy-Susini8. 1. From the Institute of Metabolic and Cardiovascular Diseases of Toulouse, Université de Toulouse (F.M., F.T., F.P., A.C.G., F.D.T., F.B., E.L., A.C.P., F.L., B.G.-S.). 2. Department of Plastic Surgery (B.C.). 3. Unité Mixte de Recherche 1037-Centre de Recherche en Cancérologie de Toulouse (N.T., J.G.-G.), Inserm, Université Paul Sabatier, France. 4. Department of Gynecology Surgery, IUCT-Oncopole, Toulouse, France (C.V.). 5. Unité Mixte de Recherche Centre National de la Recherche Scientifique 6290, Rennes, France (R.M.). 6. Department of Vascular Medicine (J.M.-D.), Centre Hospitalo-Universitaire Rangueil, Toulouse, France. 7. Centre National de la Recherche Scientifique, Laboratoire d'analyse et d'architecture des systèmes, Toulouse, France (K.G., D.D.). 8. From the Institute of Metabolic and Cardiovascular Diseases of Toulouse, Université de Toulouse (F.M., F.T., F.P., A.C.G., F.D.T., F.B., E.L., A.C.P., F.L., B.G.-S.) barbara.garmy-susini@inserm.fr.
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 17β estradiol-the most potent endogenous estrogen-in lymphedema-a 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 backflow-a representative feature of the pathology. Blocking ERα by tamoxifen-the selective estrogen modulator-led 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 ERα in Tie2-Cre; ERαlox/lox mice, which exhibit dilated lymphatic vessels. This remodeling correlated with a decrease in lymphangiogenic gene expression. In vitro, blocking ERα 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 ERα 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.
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 17β estradiol-the most potent endogenous estrogen-in lymphedema-a 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 backflow-a representative feature of the pathology. Blocking ERα by tamoxifen-the selective estrogen modulator-led 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 ERα in Tie2-Cre; ERαlox/loxmice, which exhibit dilated lymphatic vessels. This remodeling correlated with a decrease in lymphangiogenic gene expression. In vitro, blocking ERα 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 ERα 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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