Considering that the integrity of LEC junctions is critical to lymphatic drainage efficiency, E2-induced downregulation of ZO-1 may explain the increased susceptibility to lymphedema observed in women: during puberty, E2 level will rise and, through ZO-1 inhibition, increase the permeability of a lymphatic vasculature already hampered by a genetic mutation, thus triggering lymphedema development [66]. Here, TJP1 is linked to lymphedema.