Submitted October 25, 2007
Accepted February 23, 2008
Inhibition of endogenous TGF-
signaling enhances lymphangiogenesis
Masako Oka, Caname Iwata, Hiroshi I Suzuki, Kunihiko Kiyono, Yasuyuki Morishita, Tetsuro Watabe, Akiyoshi Komuro, Mitsunobu R Kano, and Kohei Miyazono*
Department of Molecular Pathology, University of Tokyo, Tokyo, Japan
* Corresponding author; email: miyazono-ind{at}umin.ac.jp.
Lymphangiogenesis is induced by various growth factors, including VEGF-C. Although TGF-
plays crucial roles in angiogenesis, the roles of TGF- signaling in lymphangiogenesis are unknown. We show here that TGF- transduced signals in human dermal lymphatic microvascular endothelial cells (HDLECs), and inhibited the proliferation, cord formation, and migration towards VEGF-C of HDLECs. Expression of lymphatic endothelial cell (LEC) markers, including LYVE-1 and Prox1 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-, but were induced by TGF- type I receptor (TR-I) inhibitor. Moreover, inhibition of endogenous TGF- signaling by TR-I inhibitor accelerated lymphangiogenesis in a mouse model of chronic peritonitis. Lymphangiogenesis was also induced by TR-I inhibitor in the presence of VEGF-C in pancreatic adenocarcinoma xenograft models inoculated in nude mice. These findings suggest that TGF- transduces signals in LECs and plays an important role in the regulation of lymphangiogenesis in vivo.
