Skip to main content

Advertisement

Log in

Lymphatic vessels: new targets for the treatment of inflammatory diseases

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

The lymphatic system plays an important role in the physiological control of the tissue fluid balance and in the initiation of immune responses. Recent studies have shown that lymphangiogenesis, the growth of new lymphatic vessels and/or the expansion of existing lymphatic vessels, is a characteristic feature of acute inflammatory reactions and of chronic inflammatory diseases. In these conditions, lymphatic vessel expansion occurs at the tissue level but also within the draining lymph nodes. Surprisingly, activation of lymphatic vessel function by delivery of vascular endothelial growth factor-C exerts anti-inflammatory effects in several models of cutaneous and joint inflammation. These effects are likely mediated by enhanced drainage of extravasated fluid and inflammatory cells, but also by lymphatic vessel-mediated modulation of immune responses. Although some of the underlying mechanisms are just beginning to be identified, lymphatic vessels have emerged as important targets for the development of new therapeutic strategies to treat inflammatory conditions. In this context, it is of great interest that some of the currently used anti-inflammatory drugs also potently activate lymphatic vessels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Albrecht I, Christofori G (2011) Molecular mechanisms of lymphangiogenesis in development and cancer. Int J Dev Biol 55(4–5):483–494. doi:10.1387/ijdb.103226ia

    Article  PubMed  CAS  Google Scholar 

  2. Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17(11):1371–1380. doi:10.1038/nm.2545

    Article  PubMed  CAS  Google Scholar 

  3. Cueni LN, Detmar M (2006) New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 126(10):2167–2177. doi:10.1038/sj.jid.5700464

    Article  PubMed  CAS  Google Scholar 

  4. Halin C, Detmar M (2008) Chapter 1. Inflammation, angiogenesis, and lymphangiogenesis. Methods Enzymol 445:1–25. doi:10.1016/S0076-6879(08)03001-2

    Article  PubMed  CAS  Google Scholar 

  5. Hirakawa S, Hong YK, Harvey N, Schacht V, Matsuda K, Libermann T, Detmar M (2003) Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162(2):575–586. doi:10.1016/S0002-9440(10)63851-5

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Kriehuber E, Breiteneder-Geleff S, Groeger M, Soleiman A, Schoppmann SF, Stingl G, Kerjaschki D, Maurer D (2001) Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 194(6):797–808

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21(17):4593–4599

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20(17):4762–4773. doi:10.1093/emboj/20.17.4762

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140(4):460–476. doi:10.1016/j.cell.2010.01.045

    Article  PubMed  CAS  Google Scholar 

  10. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92(8):3566–3570

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, Stacker SA, Achen MG, Alitalo K (2000) VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 14(13):2087–2096. doi:10.1096/fj.99-1049com

    Article  PubMed  CAS  Google Scholar 

  12. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98(6):769–778

    Article  PubMed  CAS  Google Scholar 

  13. Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, Libermann T, Dezube BJ, Fingeroth JD, Detmar M (2004) Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36(7):683–685

    Article  PubMed  CAS  Google Scholar 

  14. Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144(4):789–801

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Gale NW, Prevo R, Espinosa J, Ferguson DJ, Dominguez MG, Yancopoulos GD, Thurston G, Jackson DG (2007) Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol 27(2):595–604. doi:10.1128/MCB.01503-06

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19(3):397–410. doi:10.1101/gad.330105

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Mouta Carreira C, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI, Jain RK (2001) LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res 61(22):8079–8084

    PubMed  CAS  Google Scholar 

  18. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154(2):385–394. doi:10.1016/S0002-9440(10)65285-6

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22(14):3546–3556. doi:10.1093/emboj/cdg342

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Wick N, Haluza D, Gurnhofer E, Raab I, Kasimir MT, Prinz M, Steiner CW, Reinisch C, Howorka A, Giovanoli P, Buchsbaum S, Krieger S, Tschachler E, Petzelbauer P, Kerjaschki D (2008) Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am J Pathol 173(4):1202–1209. doi:10.2353/ajpath.2008.080101

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Hamrah P, Chen L, Zhang Q, Dana MR (2003) Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol 163(1):57–68. doi:10.1016/S0002-9440(10)63630-9

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Cursiefen C, Chen L, Saint-Geniez M, Hamrah P, Jin Y, Rashid S, Pytowski B, Persaud K, Wu Y, Streilein JW, Dana R (2006) Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci U S A 103(30):11405–11410. doi:10.1073/pnas.0506112103

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Burke Z, Oliver G (2002) Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 118(1–2):147–155

    Article  PubMed  CAS  Google Scholar 

  24. Lavado A, Oliver G (2007) Prox1 expression patterns in the developing and adult murine brain. Dev Dyn 236(2):518–524. doi:10.1002/dvdy.21024

    Article  PubMed  CAS  Google Scholar 

  25. Galeeva A, Treuter E, Tomarev S, Pelto-Huikko M (2007) A prospero-related homeobox gene Prox-1 is expressed during postnatal brain development as well as in the adult rodent brain. Neuroscience 146(2):604–616. doi:10.1016/j.neuroscience.2007.02.002

    Article  PubMed  CAS  Google Scholar 

  26. Chen L, Cursiefen C, Barabino S, Zhang Q, Dana MR (2005) Novel expression and characterization of lymphatic vessel endothelial hyaluronate receptor 1 (LYVE-1) by conjunctival cells. Invest Ophthalmol Vis Sci 46(12):4536–4540. doi:10.1167/iovs.05-0975

    Article  PubMed Central  PubMed  Google Scholar 

  27. Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T, Schwendener RA, Brekken RA, Kang G, Oike Y, Choi TS, Suda T, Yoo OJ, Koh GY (2007) Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 100(4):e47–e57. doi:10.1161/01.RES.0000259564.92792.93

    Article  PubMed  CAS  Google Scholar 

  28. Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, Goerdt S (2006) Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 209(1):67–77. doi:10.1002/path.1942

    Article  PubMed  CAS  Google Scholar 

  29. Williams MC, Cao Y, Hinds A, Rishi AK, Wetterwald A (1996) T1 alpha protein is developmentally regulated and expressed by alveolar type I cells, choroid plexus, and ciliary epithelia of adult rats. Am J Respir Cell Mol Biol 14(6):577–585. doi:10.1165/ajrcmb.14.6.8652186

    Article  PubMed  CAS  Google Scholar 

  30. Kaji C, Tomooka M, Kato Y, Kojima H, Sawa Y (2012) The expression of podoplanin and classic cadherins in the mouse brain. J Anat 220(5):435–446. doi:10.1111/j.1469-7580.2012.01484.x

    Article  PubMed  CAS  Google Scholar 

  31. Ramirez MI, Millien G, Hinds A, Cao Y, Seldin DC, Williams MC (2003) T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev Biol 256(1):61–72

    Article  PubMed  CAS  Google Scholar 

  32. Bekiaris V, Withers D, Glanville SH, McConnell FM, Parnell SM, Kim MY, Gaspal FM, Jenkinson E, Sweet C, Anderson G, Lane PJ (2007) Role of CD30 in B/T segregation in the spleen. J Immunol 179(11):7535–7543

    Article  PubMed  CAS  Google Scholar 

  33. Malhotra D, Fletcher AL, Astarita J, Lukacs-Kornek V, Tayalia P, Gonzalez SF, Elpek KG, Chang SK, Knoblich K, Hemler ME, Brenner MB, Carroll MC, Mooney DJ, Turley SJ (2012) Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol 13(5):499–510. doi:10.1038/ni.2262

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Hou TZ, Bystrom J, Sherlock JP, Qureshi O, Parnell SM, Anderson G, Gilroy DW, Buckley CD (2010) A distinct subset of podoplanin (gp38) expressing F4/80+ macrophages mediate phagocytosis and are induced following zymosan peritonitis. FEBS Lett 584(18):3955–3961. doi:10.1016/j.febslet.2010.07.053

    Article  PubMed  CAS  Google Scholar 

  35. Kerrigan AM, Navarro-Nunez L, Pyz E, Finney BA, Willment JA, Watson SP, Brown GD (2012) Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J Thromb Haemost 10(3):484–486. doi:10.1111/j.1538-7836.2011.04614.x

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, Wucherpfennig K, Turley S, Carroll MC, Sobel RA, Bettelli E, Kuchroo VK (2011) Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35(6):986–996. doi:10.1016/j.immuni.2011.10.015

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Fujii T, Zen Y, Sato Y, Sasaki M, Enomae M, Minato H, Masuda S, Uehara T, Katsuyama T, Nakanuma Y (2008) Podoplanin is a useful diagnostic marker for epithelioid hemangioendothelioma of the liver. Mod Pathol 21(2):125–130. doi:10.1038/modpathol.3800986

    PubMed  CAS  Google Scholar 

  38. Baluk P, McDonald DM (2008) Markers for microscopic imaging of lymphangiogenesis and angiogenesis. Ann N Y Acad Sci 1131:1–12. doi:10.1196/annals.1413.001

    Article  PubMed  Google Scholar 

  39. Clasper S, Royston D, Baban D, Cao Y, Ewers S, Butz S, Vestweber D, Jackson DG (2008) A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. Cancer Res 68(18):7293–7303. doi:10.1158/0008-5472.CAN-07-6506

    Article  PubMed  CAS  Google Scholar 

  40. Groger M, Loewe R, Holnthoner W, Embacher R, Pillinger M, Herron GS, Wolff K, Petzelbauer P (2004) IL-3 induces expression of lymphatic markers Prox-1 and podoplanin in human endothelial cells. J Immunol 173(12):7161–7169

    Article  PubMed  Google Scholar 

  41. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV, Pytowski B, Stacker SA, Yla-Herttuala S, Jackson DG, Alitalo K, McDonald DM (2005) Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115(2):247–257. doi:10.1172/JCI22037

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282(46):33671–33680. doi:10.1074/jbc.M702889200

    Article  PubMed  CAS  Google Scholar 

  43. Vigl B, Aebischer D, Nitschke M, Iolyeva M, Rothlin T, Antsiferova O, Halin C (2011) Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner. Blood 118(1):205–215. doi:10.1182/blood-2010-12-326447

    Article  PubMed  CAS  Google Scholar 

  44. Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, Werner S, Alitalo K, Detmar M (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117(17):4667–4678. doi:10.1182/blood-2010-10-316356

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, Pepper MS, Zawieja DC, Ran S (2010) Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 115(2):418–429. doi:10.1182/blood-2008-12-196840

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Proulx ST, Luciani P, Dieterich LC, Karaman S, Leroux JC, Detmar M (2013) Expansion of the lymphatic vasculature in cancer and inflammation: new opportunities for in vivo imaging and drug delivery. J Control Release. doi:10.1016/j.jconrel.2013.04.027

    PubMed  Google Scholar 

  47. Kunstfeld R, Hirakawa S, Hong YK, Schacht V, Lange-Asschenfeldt B, Velasco P, Lin C, Fiebiger E, Wei X, Wu Y, Hicklin D, Bohlen P, Detmar M (2004) Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104(4):1048–1057. doi:10.1182/blood-2003-08-2964

    Article  PubMed  CAS  Google Scholar 

  48. Zhang Q, Lu Y, Proulx ST, Guo R, Yao Z, Schwarz EM, Boyce BF, Xing L (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther 9(6):R118. doi:10.1186/ar2326

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. Xu H, Edwards J, Banerji S, Prevo R, Jackson DG, Athanasou NA (2003) Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Ann Rheum Dis 62(12):1227–1229

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Shi J, Liang Q, Wang Y, Mooney R, Boyce B, Xing L (2012) Use of a whole-slide imaging system to assess the presence and alteration of lymphatic vessels in joint sections of arthritic mice. Biotech Histochem. doi:10.3109/10520295.2012.729864

    PubMed Central  Google Scholar 

  51. Shi VY, Bao L, Chan LS (2012) Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model. Microcirculation 19(7):567–579. doi:10.1111/j.1549-8719.2012.00189.x

    Article  PubMed  CAS  Google Scholar 

  52. Alexander JS, Chaitanya GV, Grisham MB, Boktor M (2010) Emerging roles of lymphatics in inflammatory bowel disease. Ann N Y Acad Sci 1207(Suppl 1):E75–E85. doi:10.1111/j.1749-6632.2010.05757.x

    Article  PubMed  Google Scholar 

  53. Jurisic G, Sundberg JP, Bleich A, Leiter EH, Broman KW, Buechler G, Alley L, Vestweber D, Detmar M (2010) Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease. Genes Immun 11(3):219–231. doi:10.1038/gene.2010.4

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196(11):1497–1506

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Mumprecht V, Roudnicky F, Detmar M (2012) Inflammation-induced lymph node lymphangiogenesis is reversible. Am J Pathol 180(3):874–879. doi:10.1016/j.ajpath.2011.11.010

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. Kelley PM, Conner AL, Tempero RM (2013) Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol. doi:10.1016/j.ajpath.2013.02.025

    Google Scholar 

  57. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201(7):1089–1099. doi:10.1084/jem.20041896

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  58. Angeli V, Ginhoux F, Llodra J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24(2):203–215. doi:10.1016/j.immuni.2006.01.003

    Article  PubMed  CAS  Google Scholar 

  59. Halin C, Tobler NE, Vigl B, Brown LF, Detmar M (2007) VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 110(9):3158–3167. doi:10.1182/blood-2007-01-066811

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, Han SH, Alitalo K, Koh GY (2009) Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113(22):5650–5659. doi:10.1182/blood-2008-09-176776

    Article  PubMed  CAS  Google Scholar 

  61. Kataru RP, Kim H, Jang C, Choi DK, Koh BI, Kim M, Gollamudi S, Kim YK, Lee SH, Koh GY (2011) T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34(1):96–107. doi:10.1016/j.immuni.2010.12.016

    Article  PubMed  CAS  Google Scholar 

  62. Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 18(10):1111–1113

    PubMed  CAS  Google Scholar 

  63. Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207(10):2255–2269. doi:10.1084/jem.20100559

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613

    PubMed Central  PubMed  CAS  Google Scholar 

  65. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell 3(3):411–423

    Article  PubMed  CAS  Google Scholar 

  66. Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, Maekawa H, Kimura Y, Ohmura M, Miyamoto T, Nozawa S, Koh GY, Alitalo K, Suda T (2005) Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105(12):4649–4656. doi:10.1182/blood-2004-08-3382

    Article  PubMed  CAS  Google Scholar 

  67. Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004) Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci U S A 101(32):11658–11663. doi:10.1073/pnas.0404272101

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Shin JW, Min M, Larrieu-Lahargue F, Canron X, Kunstfeld R, Nguyen L, Henderson JE, Bikfalvi A, Detmar M, Hong YK (2006) Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 17(2):576–584. doi:10.1091/mbc.E05-04-0368

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M (2005) Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24(16):2885–2895. doi:10.1038/sj.emboj.7600763

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6(4):333–345. doi:10.1016/j.ccr.2004.08.034

    Article  PubMed  CAS  Google Scholar 

  71. Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y (2005) Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci U S A 102(43):15593–15598. doi:10.1073/pnas.0507865102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  72. Kang S, Lee SP, Kim KE, Kim HZ, Memet S, Koh GY (2009) Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113(11):2605–2613. doi:10.1182/blood-2008-07-166934

    Article  PubMed  CAS  Google Scholar 

  73. Kim KE, Koh YJ, Jeon BH, Jang C, Han J, Kataru RP, Schwendener RA, Kim JM, Koh GY (2009) Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol 175(4):1733–1745. doi:10.2353/ajpath.2009.090133

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Baluk P, Hogmalm A, Bry M, Alitalo K, Bry K, McDonald DM (2013) Transgenic overexpression of interleukin-1beta induces persistent lymphangiogenesis but not angiogenesis in mouse airways. Am J Pathol 182(4):1434–1447. doi:10.1016/j.ajpath.2012.12.003

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Watari K, Nakao S, Fotovati A, Basaki Y, Hosoi F, Bereczky B, Higuchi R, Miyamoto T, Kuwano M, Ono M (2008) Role of macrophages in inflammatory lymphangiogenesis: enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation. Biochem Biophys Res Commun 377(3):826–831. doi:10.1016/j.bbrc.2008.10.077

    Article  PubMed  CAS  Google Scholar 

  76. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T (2009) M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 206(5):1089–1102. doi:10.1084/jem.20081605

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  77. Cha HS, Bae EK, Koh JH, Chai JY, Jeon CH, Ahn KS, Kim J, Koh EM (2007) Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes. J Rheumatol 34(1):16–19

    PubMed  Google Scholar 

  78. Chaitanya GV, Franks SE, Cromer W, Wells SR, Bienkowska M, Jennings MH, Ruddell A, Ando T, Wang Y, Gu Y, Sapp M, Mathis JM, Jordan PA, Minagar A, Alexander JS (2010) Differential cytokine responses in human and mouse lymphatic endothelial cells to cytokines in vitro. Lymphat Res Biol 8(3):155–164. doi:10.1089/lrb 2010.0004

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  79. Kajiya K, Hirakawa S, Detmar M (2006) Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 169(4):1496–1503. doi:10.2353/ajpath.2006.060197

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. Zhou Q, Wood R, Schwarz EM, Wang YJ, Xing L (2010) Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in mice. Arthritis Rheum 62(7):1881–1889. doi:10.1002/art.27464

    PubMed Central  PubMed  Google Scholar 

  81. Zhou Q, Guo R, Wood R, Boyce BF, Liang Q, Wang YJ, Schwarz EM, Xing L (2011) Vascular endothelial growth factor C attenuates joint damage in chronic inflammatory arthritis by accelerating local lymphatic drainage in mice. Arthritis Rheum 63(8):2318–2328. doi:10.1002/art.30421

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  82. Guo R, Zhou Q, Proulx ST, Wood R, Ji RC, Ritchlin CT, Pytowski B, Zhu Z, Wang YJ, Schwarz EM, Xing L (2009) Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum 60(9):2666–2676. doi:10.1002/art.24764

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Xia YP, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS (2003) Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 102(1):161–168. doi:10.1182/blood-2002-12-3793

    Article  PubMed  CAS  Google Scholar 

  84. Hirakawa S, Fujii S, Kajiya K, Yano K, Detmar M (2005) Vascular endothelial growth factor promotes sensitivity to ultraviolet B-induced cutaneous photodamage. Blood 105(6):2392–2399. doi:10.1182/blood-2004-06-2435

    Article  PubMed  CAS  Google Scholar 

  85. Kajiya K, Sawane M, Huggenberger R, Detmar M (2009) Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol 129(5):1292–1298. doi:10.1038/jid.2008.351

    Article  PubMed  CAS  Google Scholar 

  86. Kajiya K, Detmar M (2006) An important role of lymphatic vessels in the control of UVB-induced edema formation and inflammation. J Invest Dermatol 126(4):919–921. doi:10.1038/sj.jid.5700126

    Article  PubMed  CAS  Google Scholar 

  87. Jurisic G, Sundberg JP, Detmar M (2013) Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. Inflamm Bowel Dis 19:1983–1989

    PubMed  Google Scholar 

  88. Tewalt EF, Cohen JN, Rouhani SJ, Engelhard VH (2012) Lymphatic endothelial cells—key players in regulation of tolerance and immunity. Front Immunol 3:305. doi:10.3389/fimmu.2012.00305

    Article  PubMed Central  PubMed  Google Scholar 

  89. McKimmie CS, Singh MD, Hewit K, Lopez-Franco O, Le Brocq M, Rose-John S, Lee KM, Baker AH, Wheat R, Blackbourn DJ, Nibbs RJ, Graham GJ (2013) An analysis of the function and expression of D6 on lymphatic endothelial cells. Blood. doi:10.1182/blood-2012-04-425314

    PubMed  Google Scholar 

  90. Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R, Correale C, Arena V, Fantini M, Roncalli M, Malesci A, Mantovani A, Locati M, Danese S (2010) The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6. Gut 59(2):197–206. doi:10.1136/gut.2009.183772

    Article  PubMed  Google Scholar 

  91. Cyster JG, Schwab SR (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30:69–94. doi:10.1146/annurev-immunol-020711-075011

    Article  PubMed  CAS  Google Scholar 

  92. Tan KW, Yeo KP, Wong FH, Lim HY, Khoo KL, Abastado JP, Angeli V (2012) Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J Immunol 188(8):4065–4080. doi:10.4049/jimmunol.1101854

    Article  PubMed  CAS  Google Scholar 

  93. Khan O, Headley M, Gerard A, Wei W, Liu L, Krummel MF (2011) Regulation of T cell priming by lymphoid stroma. PLoS ONE 6(11):e26138. doi:10.1371/journal.pone.0026138

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  94. Lukacs-Kornek V, Malhotra D, Fletcher AL, Acton SE, Elpek KG, Tayalia P, Collier AR, Turley SJ (2011) Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol 12(11):1096–1104. doi:10.1038/ni.2112

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Podgrabinska S, Kamalu O, Mayer L, Shimaoka M, Snoeck H, Randolph GJ, Skobe M (2009) Inflamed lymphatic endothelium suppresses dendritic cell maturation and function via Mac-1/ICAM-1-dependent mechanism. J Immunol 183(3):1767–1779. doi:10.4049/jimmunol.0802167

    Article  PubMed  CAS  Google Scholar 

  96. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, Farr AG, Tung KS, Engelhard VH (2010) Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med 207(4):681–688. doi:10.1084/jem.20092465

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  97. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, Collier AR, Boyd RL, Turley SJ (2010) Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med 207(4):689–697. doi:10.1084/jem.20092642

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  98. Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, Fahl SP, Conaway MR, Bender TP, Tung KS, Vella AT, Adler AJ, Chen L, Engelhard VH (2012) Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood 120(24):4772–4782. doi:10.1182/blood-2012-04-427013

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Alitalo A, Detmar M (2012) Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31(42):4499–4508. doi:10.1038/onc.2011.602

    Article  PubMed  CAS  Google Scholar 

  100. Shimizu Y, Shibata R, Shintani S, Ishii M, Murohara T (2012) Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells. J Am Heart Assoc 1(4):e000877. doi:10.1161/JAHA.112.000877

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  101. Choi I, Lee YS, Chung HK, Choi D, Ecoiffier T, Lee HN, Kim KE, Lee S, Park EK, Maeng YS, Kim NY, Ladner RD, Petasis NA, Koh CJ, Chen L, Lenz HJ, Hong YK (2013) Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis 16(1):29–44. doi:10.1007/s10456-012-9297-6

    Article  PubMed  CAS  Google Scholar 

  102. Choi I, Lee S, Kyoung Chung H, Suk Lee Y, Eui Kim K, Choi D, Park EK, Yang D, Ecoiffier T, Monahan J, Chen W, Aguilar B, Lee HN, Yoo J, Koh CJ, Chen L, Wong AK, Hong YK (2012) 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema. Circulation 125(7):872–882. doi:10.1161/CIRCULATIONAHA.111.030296

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  103. Marino D, Dabouras V, Brändli AW, Detmar M (2011) A role for all-trans-retinoic acid in the early steps of lymphatic vasculature development. J Vasc Res 48:236–251

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  104. Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, Miyazono K (2007) Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 67(21):10181–10189. doi:10.1158/0008-5472.CAN-07-2366

    Article  PubMed  CAS  Google Scholar 

  105. Kashiwagi S, Hosono K, Suzuki T, Takeda A, Uchinuma E, Majima M (2011) Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema. Lab Invest 91(9):1314–1325. doi:10.1038/labinvest.2011.84

    Article  PubMed  CAS  Google Scholar 

  106. Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, Rupasinghe TW, Tull DL, Baldwin ME, Sloan EK, Fox SB, Achen MG, Stacker SA (2012) VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 21(2):181–195. doi:10.1016/j.ccr.2011.12.026

    Article  PubMed  CAS  Google Scholar 

  107. Yao LC, Baluk P, Feng J, McDonald DM (2010) Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 176(3):1525–1541. doi:10.2353/ajpath.2010.090909

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  108. Steele MM, Kelley PM, Schieler AM, Tempero RM (2011) Glucocorticoids suppress corneal lymphangiogenesis. Cornea 30(12):1442–1447. doi:10.1097/ICO.0b013e318213f39f

    Article  PubMed  Google Scholar 

  109. Hos D, Saban DR, Bock F, Regenfuss B, Onderka J, Masli S, Cursiefen C (2011) Suppression of inflammatory corneal lymphangiogenesis by application of topical corticosteroids. Arch Ophthalmol 129(4):445–452. doi:10.1001/archophthalmol.2011.42

    Article  PubMed  CAS  Google Scholar 

  110. Yano A, Fujii Y, Iwai A, Kawakami S, Kageyama Y, Kihara K (2006) Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Clin Cancer Res 12(20 Pt 1):6012–6017. doi:10.1158/1078-0432.CCR-06-0749

    Article  PubMed  CAS  Google Scholar 

  111. Okanobo A, Chauhan SK, Dastjerdi MH, Kodati S, Dana R (2012) Efficacy of topical blockade of interleukin-1 in experimental dry eye disease. Am J Ophthalmol 154(1):63–71. doi:10.1016/j.ajo.2012.01.034

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  112. Shinriki S, Jono H, Ueda M, Ota K, Ota T, Sueyoshi T, Oike Y, Ibusuki M, Hiraki A, Nakayama H, Shinohara M, Ando Y (2011) Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J Pathol 225(1):142–150. doi:10.1002/path.2935

    Article  PubMed  CAS  Google Scholar 

  113. Polzer K, Baeten D, Soleiman A, Distler J, Gerlag DM, Tak PP, Schett G, Zwerina J (2008) Tumour necrosis factor blockade increases lymphangiogenesis in murine and human arthritic joints. Ann Rheum Dis 67(11):1610–1616. doi:10.1136/ard.2007.083394

    Article  PubMed  CAS  Google Scholar 

  114. Schulz MM, Reisen F, Zgraggen S, Fischer S, Yuen D, Kang GJ, Chen L, Schneider G, Detmar M (2012) Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis. Proc Natl Acad Sci U S A 109(40):E2665–E2674. doi:10.1073/pnas.1206036109

    Article  PubMed Central  PubMed  Google Scholar 

  115. Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, Yan L, Shealy DJ, McDonald DM (2009) TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest 119(10):2954–2964. doi:10.1172/JCI37626

    PubMed Central  PubMed  CAS  Google Scholar 

  116. Fiorentini S, Luganini A, Dell’Oste V, Lorusso B, Cervi E, Caccuri F, Bonardelli S, Landolfo S, Caruso A, Gribaudo G (2011) Human cytomegalovirus productively infects lymphatic endothelial cells and induces a secretome that promotes angiogenesis and lymphangiogenesis through interleukin-6 and granulocyte-macrophage colony-stimulating factor. J Gen Virol 92(Pt 3):650–660. doi:10.1099/vir.0.025395-0

    Article  PubMed  CAS  Google Scholar 

  117. Chen X, Xie Q, Cheng X, Diao X, Cheng Y, Liu J, Xie W, Chen Z, Zhu B (2010) Role of interleukin-17 in lymphangiogenesis in non-small-cell lung cancer: enhanced production of vascular endothelial growth factor C in non-small-cell lung carcinoma cells. Cancer Sci 101(11):2384–2390. doi:10.1111/j.1349-7006.2010.01684.x

    Article  PubMed  CAS  Google Scholar 

  118. Chauhan SK, Jin Y, Goyal S, Lee HS, Fuchsluger TA, Lee HK, Dana R (2011) A novel pro-lymphangiogenic function for Th17/IL-17. Blood 118(17):4630–4634. doi:10.1182/blood-2011-01-332049

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  119. Yamashita M, Iwama N, Date F, Shibata N, Miki H, Yamauchi K, Sawai T, Sato S, Takahashi T, Ono M (2009) Macrophages participate in lymphangiogenesis in idiopathic diffuse alveolar damage through CCL19-CCR7 signal. Hum Pathol 40(11):1553–1563. doi:10.1016/j.humpath.2009.03.021

    Article  PubMed  CAS  Google Scholar 

  120. Zhuo W, Jia L, Song N, Lu XA, Ding Y, Wang X, Song X, Fu Y, Luo Y (2012) The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis. Clin Cancer Res 18(19):5387–5398. doi:10.1158/1078-0432.CCR-12-0708

    Article  PubMed  CAS  Google Scholar 

  121. Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML (2004) Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res 64(2):554–564

    Article  PubMed  CAS  Google Scholar 

  122. Hosono K, Suzuki T, Tamaki H, Sakagami H, Hayashi I, Narumiya S, Alitalo K, Majima M (2011) Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation. Arterioscler Thromb Vasc Biol 31(5):1049–1058. doi:10.1161/ATVBAHA.110.222356

    Article  PubMed  CAS  Google Scholar 

  123. Kajiya K, Huggenberger R, Drinnenberg I, Ma B, Detmar M (2008) Nitric oxide mediates lymphatic vessel activation via soluble guanylate cyclase alpha1beta1-impact on inflammation. FASEB J 22(2):530–537. doi:10.1096/fj.07-8873com

    Article  PubMed  CAS  Google Scholar 

  124. Lahdenranta J, Hagendoorn J, Padera TP, Hoshida T, Nelson G, Kashiwagi S, Jain RK, Fukumura D (2009) Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 69(7):2801–2808. doi:10.1158/0008-5472.CAN-08-4051

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Alexandra Ochsenbein for providing tissue sections. Work in the authors’ laboratory is supported by the Swiss National Science Foundation, the European Research Council, the ETH Zurich, the Krebsliga Zürich and the Krebsliga Schweiz.

Conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Detmar.

Additional information

Lothar C. Dieterich and Catharina D. Seidel have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dieterich, L.C., Seidel, C.D. & Detmar, M. Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 17, 359–371 (2014). https://doi.org/10.1007/s10456-013-9406-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-013-9406-1

Keywords

Navigation