Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

Am J Physiol Cell Physiol. 2012 Jan 15;302(2):C392-404. doi: 10.1152/ajpcell.00306.2011. Epub 2011 Sep 21.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Female
  • Hepatocyte Growth Factor / metabolism*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / metabolism
  • Lymph / metabolism
  • Lymphangiogenesis / physiology*
  • Lymphatic System / pathology
  • Lymphatic System / physiology*
  • Lymphatic System / physiopathology
  • Lymphedema / metabolism
  • Lymphedema / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Regeneration / physiology
  • T-Lymphocytes / immunology
  • Tail / anatomy & histology
  • Tail / metabolism
  • Tail / pathology
  • Tail / physiopathology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor C / metabolism*


  • Cytokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Hepatocyte Growth Factor
  • Interferon-gamma