Lymphedema pp 43-48 | Cite as

Embryology of the Lymphatic System and Lymphangiogenesis

  • Stanley G. Rockson


The lymphatic vasculature was first described by Aselli more than three centuries ago, and the hypothesized embryonic origin of the lymphatic structures was initially investigated in 19021; nevertheless, it only has been recently, during the era of molecular biology, that the mechanisms of mammalian lymphatic development have become well understood.2,3


Lymphatic Endothelial Cell Cardinal Vein Lymphatic Vasculature Prox1 Expression Molecular Therapeutics 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author gratefully acknowledges Shauna Rockson for her artistic contribution to this chapter.


  1. 1.
    Kanter MA. The lymphatic system: an historical perspective. Plast Reconstr Surg. 1987;79(1):131-139.PubMedCrossRefGoogle Scholar
  2. 2.
    Nakamura K, Rockson SG. Biomarkers of lymphatic function and disease: state of the art and future directions. Mol Diagn Ther. 2007;11(4):227-238.PubMedGoogle Scholar
  3. 3.
    Nakamura K, Rockson SG. Molecular targets for therapeutic lymphangiogenesis in lymphatic dysfunction and disease. Lymphat Res Biol. 2008;6(3–4):181-189.PubMedCrossRefGoogle Scholar
  4. 4.
    Witte MH, Jones K, Wilting J, et al. Structure function relationships in the lymphatic system and implications for cancer biology. Cancer Metastasis Rev. 2006;25(2):159-184.PubMedCrossRefGoogle Scholar
  5. 5.
    van der Putte S. The development of the lymphatic system in man. Adv Anat Embryol Cell Biol. 1975;51:3-60.PubMedGoogle Scholar
  6. 6.
    Cueni LN, Detmar M. The lymphatic system in health and disease. Lymphat Res Biol. 2008;6(3–4):109-122.PubMedCrossRefGoogle Scholar
  7. 7.
    Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999;98(6):769-778.PubMedCrossRefGoogle Scholar
  8. 8.
    Wigle JT, Harvey N, Detmar M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002;21(7):1505-1513.PubMedCrossRefGoogle Scholar
  9. 9.
    Srinivasan RS, Dillard ME, Lagutin OV, et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007;21(19):2422-2432.PubMedCrossRefGoogle Scholar
  10. 10.
    Yaniv K, Isogai S, Castranova D, Dye L, Hitomi J, Weinstein BM. Live imaging of lymphatic development in the zebrafish. Nat Med. 2006;12(6):711-716.PubMedCrossRefGoogle Scholar
  11. 11.
    Schneider M, Othman-Hassan K, Christ B, Wilting J. Lymphangioblasts in the avian wing bud. Dev Dyn. 1999;216(4–5):311-319.PubMedCrossRefGoogle Scholar
  12. 12.
    Wilting J, Aref Y, Huang R, et al. Dual origin of avian lymphatics. Dev Biol. 2006;292(1):165-173.PubMedCrossRefGoogle Scholar
  13. 13.
    Ny A, Koch M, Schneider M, et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat Med. 2005;11(9):998-1004.PubMedGoogle Scholar
  14. 14.
    Buttler K, Kreysing A, von Kaisenberg CS, et al. Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos. Dev Dyn. 2006;235(6):1554-1562.PubMedCrossRefGoogle Scholar
  15. 15.
    Oliver G. Lymphatic vasculature development. Nat Rev Immunol. 2004;4(1):35-45.PubMedCrossRefGoogle Scholar
  16. 16.
    Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000;60(2):203-212.PubMedGoogle Scholar
  17. 17.
    Cueni LN, Detmar M. New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol. 2006;126(10):2167-2177.PubMedCrossRefGoogle Scholar
  18. 18.
    Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5(1):74-80.PubMedCrossRefGoogle Scholar
  19. 19.
    Francois M, Caprini A, Hosking B, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008;456(7222):643-647.PubMedCrossRefGoogle Scholar
  20. 20.
    Yamazaki T, Yoshimatsu Y, Morishita Y, Miyazono K, Watabe T. COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction. Genes Cells. 2009;14(3):425-434.PubMedCrossRefGoogle Scholar
  21. 21.
    Lee S, Kang J, Yoo J, et al. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood. 2009;113(8):1856-1859.PubMedCrossRefGoogle Scholar
  22. 22.
    Srinivasan RS, Geng X, Yang Y, et al. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev. 2010;24(7):696-707.PubMedCrossRefGoogle Scholar
  23. 23.
    Abtahian F, Guerriero A, Sebzda E, et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science. 2003;299(5604):247-251.PubMedCrossRefGoogle Scholar
  24. 24.
    Bertozzi CC, Hess PR, Kahn ML. Platelets: covert regulators of lymphatic development. Arterioscler Thromb Vasc Biol. 2010;30(12):2368-2371.PubMedCrossRefGoogle Scholar
  25. 25.
    Bertozzi CC, Schmaier AA, Mericko P, et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood. 2010;116(4):661-670.PubMedCrossRefGoogle Scholar
  26. 26.
    Petrova TV, Karpanen T, Norrmen C, et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med. 2004;10(9):974-981.PubMedCrossRefGoogle Scholar
  27. 27.
    Norrmen C, Ivanov KI, Cheng J, et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol. 2009;185(3):439-457.PubMedCrossRefGoogle Scholar
  28. 28.
    Makinen T, Adams RH, Bailey J, et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 2005;19(3):397-410.PubMedCrossRefGoogle Scholar
  29. 29.
    Gale N, Thurston G, Hackett S, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev Cell. 2002;3:411-423.PubMedCrossRefGoogle Scholar
  30. 30.
    Shimoda H, Bernas MJ, Witte MH, Gale NW, Yancopoulos GD, Kato S. Abnormal recruitment of periendothelial cells to lymphatic capillaries in digestive organs of angiopoietin-2-deficient mice. Cell Tissue Res. 2007;328(2):329-337.PubMedCrossRefGoogle Scholar
  31. 31.
    Dellinger M, Hunter R, Bernas M, et al. Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice. Dev Biol. 2008;319(2):309-320.PubMedCrossRefGoogle Scholar
  32. 32.
    Bazigou E, Xie S, Chen C, et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 2009;17(2):175-186.PubMedCrossRefGoogle Scholar
  33. 33.
    Saaristo A, Tammela T, Farkkila A, et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol. 2006;169(3):1080-1087.PubMedCrossRefGoogle Scholar
  34. 34.
    Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol. 2008;3:367-397.PubMedCrossRefGoogle Scholar
  35. 35.
    An A, Rockson SG. The potential for molecular treatment strategies in lymphatic disease. Lymphat Res Biol. 2004;2(4):173-181.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2011

Authors and Affiliations

  • Stanley G. Rockson
    • 1
  1. 1.Division of Cardiovascular MedicineStanford University School of Medicine, Falk Cardiovascular Research CenterStanfordUSA

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