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


Authors: Zampell, J. C.; Avraham, T.; Yoder, N.; Fort, N.; Yan, A.; Weitman, E. S.; Mehrara, B. J.
Article Title: Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines
Abstract: 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. © 2012 the American Physiological Society.
Keywords: controlled study; protein expression; vascular endothelial growth factor a; nonhuman; lymphoscintigraphy; cell proliferation; t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; mus; animal experiment; animal model; inflammation; wild type; mice, inbred c57bl; mus musculus; vasculotropin c; lymph vessel; lymphangiogenesis; lymphedema; tail; wound healing; regeneration; vascular endothelial growth factor c; lymphatic system; cytokines; gamma interferon; mice, nude; vasculotropin a; transforming growth factor beta1; cytokine production; interferon-gamma; cd3+ t lymphocyte; tubulin; t lymphocyte activation; cd45 antigen; lymph; neutralizing antibody; endostatin; hepatocyte growth factor; vascular endothelial growth factor-c; interferon-?; transforming growth factor-?1
Journal Title: American Journal of Physiology - Cell Physiology
Volume: 302
Issue: 2
ISSN: 0363-6143
Publisher: American Physiological Society  
Date Published: 2012-01-01
Start Page: C392
End Page: C404
Language: English
DOI: 10.1152/ajpcell.00306.2011
PROVIDER: scopus
PUBMED: 21940662
PMCID: PMC3328842
DOI/URL:
Notes: --- - "Export Date: 1 February 2012" - "CODEN: AJPCD" - "Source: Scopus"
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MSK Authors
  1. Babak Mehrara
    295 Mehrara
  2. Tomer Avraham
    33 Avraham
  3. Jamie Christine Zampell
    29 Zampell
  4. Alan Yan
    20 Yan
  5. Evan Scott Weitman
    18 Weitman
  6. Nicole Denise Yoder
    1 Yoder
  7. Nicholas M Fort
    1 Fort