Lymphatic vasculature requires estrogen receptor alpha signaling to protect from lymphedema

Rationale: Estrogen play a crucial role on the cardiovascular system and, particularly, on the vascular endothelium. However, the effect of estrogen on the lymphatic system has been poorly investigated.
Objective: We aimed to demonstrate the protective effect of the 17 estradiol (E2), the most potent endogenous estrogen in lymphedema, a lymphatic dysfunction, which results in a massive fluid and fat accumulation.
Methods and Results: Immunohistochemistry revealed that high doses of E2 modified skin microenvironment and stimulated lymphangiogenesis. E2 activates lymphatic endothelium through a transcriptional activation induced by its receptor ER. Using an original model of secondary lymphedema, we found a protective effect of E2 that prevents limb swelling. Loss of ER function using selective estrogen modulator (SERM) and in Tie2 Cre(+); ER-/- mice lead to a disruption of the lymphatic network promoting lymphedema. This effect was associated with a remodeling of LEC, an inhibition of gene expression, and ERK, but not AKT E2-induced phosphorylation.
Conclusion: These findings reveal a new facet of the influence of estrogens in the management of the lymphatic system in pathological condition and provides more evidences that secondary lymphedema is not only a side effect of surgery, but is worsen by hormone therapy.