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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