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.
authors.affiliation: The Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Zampell
authors.forename: Tomer
authors.initials: T
authors.lastname: Avraham
authors.forename: Nicole
authors.initials: N
authors.lastname: Yoder
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fort
authors.forename: Alan
authors.initials: A
authors.lastname: Yan
authors.forename: Evan S
authors.initials: ES
authors.lastname: Weitman
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D008196:Lymph / Q000378:metabolism; D042583:Lymphangiogenesis / Q000502:physiology*; D008208:Lymphatic System / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D008209:Lymphedema / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D012038:Regeneration / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D013623:Tail / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma