Inhibition of Endogenous TGF-beta Signaling Enhances Lymphangiogenesis

Blood. 2008 May 1;111(9):4571-9. doi: 10.1182/blood-2007-10-120337. Epub 2008 Feb 29.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Lymphangiogenesis*
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms
  • Peritonitis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Signal Transduction*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor C

Substances

  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor C
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I