Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines Academic Article uri icon


MeSH Major

  • Cytokines
  • Hepatocyte Growth Factor
  • Lymphangiogenesis
  • Lymphatic System
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C


  • Lymphangiogenic cytokines such as vascular endothelial growth factor-C (VEGF-C) are critically required for lymphatic regeneration; however, in some circumstances, lymphatic function is impaired despite normal or elevated levels of these cytokines. The recent identification of anti-lymphangiogenic molecules such as interferon-γ (IFN-γ), transforming growth factor-β1, and endostatin has led us to hypothesize that impaired lymphatic function may represent a dysregulated balance in the expression of pro/anti-lymphangiogenic stimuli. We observed that nude mice have significantly improved lymphatic function compared with wild-type mice in a tail model of lymphedema. We show that gradients of lymphatic fluid stasis regulate the expression of lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) and that paradoxically the expression of these molecules is increased in wild-type mice. More importantly, we show that as a consequence of T-cell-mediated inflammation, these same gradients also regulate expression patterns of anti-lymphangiogenic molecules corresponding temporally and spatially with impaired lymphatic function in wild-type mice. We show that neutralization of IFN-γ significantly increases inflammatory lymph node lymphangiogenesis independently of changes in VEGF-A or VEGF-C expression, suggesting that alterations in the balance of pro- and anti-lymphangiogenic cytokine expression can regulate lymphatic vessel formation. In conclusion, we show that gradients of lymphatic fluid stasis regulate not only the expression of pro-lymphangiogenic cytokines but also potent suppressors of lymphangiogenesis as a consequence of T-cell inflammation and that modulation of the balance between these stimuli can regulate lymphatic function.

publication date

  • January 2012



  • Academic Article



  • eng

PubMed Central ID

  • PMC3328842

Digital Object Identifier (DOI)

  • 10.1152/ajpcell.00306.2011

PubMed ID

  • 21940662

Additional Document Info

start page

  • C392

end page

  • 404


  • 302


  • 2