Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis.
Lymphangiogenesis is induced by various growth factors, including VEGF-C. Although TGF-beta plays crucial roles in angiogenesis, the roles of TGF-beta signaling in lymphangiogenesis are unknown. We show here that TGF-beta 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 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-beta but were induced by TGF-beta type I receptor (TbetaR-I) inhibitor. Moreover, inhibition of endogenous TGF-beta signaling by TbetaR-I inhibitor accelerated lymphangiogenesis in a mouse model of chronic peritonitis. Lymphangiogenesis was also induced by TbetaR-I inhibitor in the presence of VEGF-C in pancreatic adenocarcinoma xenograft models inoculated in nude mice. These findings suggest that TGF-beta transduces signals in LECs and plays an important role in the regulation of lymphangiogenesis in vivo.
Oka
Masako
M
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Iwata
Caname
C
Suzuki
Hiroshi I
HI
Kiyono
Kunihiko
K
Morishita
Yasuyuki
Y
Watabe
Tetsuro
T
Komuro
Akiyoshi
A
Kano
Mitsunobu R
MR
Miyazono
Kohei
K
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D042583:Lymphangiogenesis; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms; D010538:Peritonitis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D042582:Vascular Endothelial Growth Factor C
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D042582:Vascular Endothelial Growth Factor C; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I