Fig. 7.

Schematic representation of FK506-induced lymphatic dysfunction. Calcineurin dephosphorylates NFAT proteins and induces translocation of NFAT into the nucleus (Hogan et al., 2003). This leads to increased transcription of NFAT target gene. Our study demonstrated that LYVE-1 is one of the target gene regulated by NFAT. This increases LVYE-1 receptor expression in lymphatic endothelial cells (LEC), where LYVE-1 plays an important role in HA-uptake and clearance. In LEC in vitro, FK506, a calcineurin inhibitor, prevents the nuclear translocation of NFAT, resulting in reduced LYVE-1 expression and, consequently, reduction in HA uptake. Additionally, FK506 treatment also reduces TERT expression, which results increased cellular senescence implicated by increased P21 expression in LEC