Inhibition of endogenous TGF-² signaling enhances lymphangiogenesis

Lymphangiogenesis is induced by various growth factors, including VEGF-C. Although TGF-β plays crucial roles in angiogenesis, the roles of TGF-β signaling in lymphangiogenesis are unknown. We show here that TGF-β transduced signals in human dermal lymphatic microvascular endothelial cells (HDLECs) and inhibited the proliferation, cord formation, and migration toward VEGF-C of HDLECs. Expression of lymphatic endothelial cell (LEC) markers, including LYVE-1 and Proxl in HDLECs, as well as early lymph vessel development in mouse embryonic stem cells in the presence of VEGF-A and C, were repressed by TGF-β but were induced by TGF-β type I receptor (TβR-I) inhibitor. Moreover, inhibition of endogenous TGF-β signaling by TpR-l inhibitor accelerated lymphangiogenesis in a mouse model of chronic peritonitis. Lymphangiogenesis was also induced by TβR-l inhibitor in the presence of VEGF-C in pancreatic adenocarcinoma xenograft models inoculated in nude mice. These findings suggest that TGF-β transduces signals in LECs and plays an important role in the regulation of lymphangiogenesis in vivo.