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Embryology of the Lymphatic System and Lymphangiogenesis

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Lymphedema

Abstract

Recent molecular and structural insights have helped to shed light on the embryological origins of the lymphatic vasculature. These discoveries have distinct implications, not only for molecular therapeutics in lymphatic vascular disease but also for the broad field of tumor biology and for the study of vascular malformations.

  • The lymphatic vessels appear substantially later than the blood vascular structures.

  • The lymphatics arise from aggregates of endothelial cells through the combined forces of vasculogenesis and angiogenesis. The earliest identifiable embryonic lymphatic precursors are the jugular lymph sacs, paired structures that are adjacent to the jugular section of the cardinal vein.

  • Both centrifugal and centripetal models for lymphatic vascular development have been proposed, and both likely play a role in mammalian biology.

  • Lymphatic vasculogenesis is thought to occur in four identifiably distinct stages: lymphatic competence, commitment, specification, and vascular coalescence and maturation.

  • Lymphangiogenesis is a critical pathway in embryonic development that has an important, clinically relevant counterpart in wound healing and inflammation.

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Highlighted References

  1. Nakamura K, Rockson SG. Molecular targets for therapeutic lymphangiogenesis in lymphatic dysfunction and disease. Lymphat Res Biol. 2008;6(3–4):181–9.

    Article  PubMed  Google Scholar 

  2. Kazenwadel J, Harvey NL. Morphogenesis of the lymphatic vasculature: a focus on new progenitors and cellular mechanisms important for constructing lymphatic vessels. Dev Dyn. 2016;245(3):209–19.

    Article  PubMed  Google Scholar 

  3. Secker GA, Harvey NL. VEGFR signaling during lymphatic vascular development: from progenitor cells to functional vessels. Dev Dyn. 2015;244(3):323–31.

    Article  CAS  PubMed  Google Scholar 

  4. Cueni LN, Detmar M. The lymphatic system in health and disease. Lymphat Res Biol. 2008;6(3–4):109–22.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oliver G. Lymphatic vasculature development. Nat Rev Immunol. 2004;4(1):35–45.

    Article  CAS  PubMed  Google Scholar 

References

  1. Kanter MA. The lymphatic system: an historical perspective. Plast Reconstr Surg. 1987;79(1):131–9.

    Article  CAS  PubMed  Google Scholar 

  2. Nakamura K, Rockson SG. Biomarkers of lymphatic function and disease: state of the art and future directions. Mol Diagn Ther. 2007;11(4):227–38.

    Article  CAS  PubMed  Google Scholar 

  3. Witte MH, Jones K, Wilting J, Dictor M, Selg M, McHale N, et al. Structure function relationships in the lymphatic system and implications for cancer biology. Cancer Metastasis Rev. 2006;25(2):159–84.

    Article  PubMed  Google Scholar 

  4. van der Putte S. The development of the lymphatic system in man. Adv Anat Embryol Cell Biol. 1975;51:3–60.

    PubMed  Google Scholar 

  5. Wigle JT, Chowdhury K, Gruss P, Oliver G. Prox1 function is crucial for mouse lens-fibre elongation. Nat Genet. 1999;21(3):318–22.

    Article  CAS  PubMed  Google Scholar 

  6. Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002;21(7):1505–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007;21(19):2422–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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):711–6.

    Article  CAS  PubMed  Google Scholar 

  9. Buttler K, Kreysing A, von Kaisenberg CS, Schweigerer L, Gale N, Papoutsi M, et al. Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos. Dev Dyn. 2006;235(6):1554–62.

    Article  CAS  PubMed  Google Scholar 

  10. Pudliszewski M, Pardanaud L. Vasculogenesis and angiogenesis in the mouse embryo studied using quail/mouse chimeras. Int J Dev Biol. 2005;49(2–3):355–61.

    Article  CAS  PubMed  Google Scholar 

  11. Wilting J, Aref Y, Huang R, Tomarev SI, Schweigerer L, Christ B, et al. Dual origin of avian lymphatics. Dev Biol. 2006;292(1):165–73.

    Article  CAS  PubMed  Google Scholar 

  12. Hogan BM, Bos FL, Bussmann J, Witte M, Chi NC, Duckers HJ, et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet. 2009;41(4):396–8.

    Article  CAS  PubMed  Google Scholar 

  13. Bos FL, Caunt M, Peterson-Maduro J, Planas-Paz L, Kowalski J, Karpanen T, et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ Res. 2011;109(5):486–91.

    Article  CAS  PubMed  Google Scholar 

  14. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000;60(2):203–12.

    CAS  PubMed  Google Scholar 

  15. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001;20(17):4762–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Salameh A, Galvagni F, Bardelli M, Bussolino F, Oliviero S. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood. 2005;106(10):3423–31.

    Article  CAS  PubMed  Google Scholar 

  17. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, 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.

    Article  CAS  PubMed  Google Scholar 

  18. Planas-Paz L, Strilic B, Goedecke A, Breier G, Fassler R, Lammert E. Mechanoinduction of lymph vessel expansion. EMBO J. 2012;31(4):788–804.

    Article  CAS  PubMed  Google Scholar 

  19. Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008;456(7222):643–7.

    Article  CAS  PubMed  Google Scholar 

  20. Srinivasan RS, Geng X, Yang Y, Wang Y, Mukatira S, Studer M, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang Y, Garcia-Verdugo JM, Soriano-Navarro M, Srinivasan RS, Scallan JP, Singh MK, et al. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood. 2012;120(11):2340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Francois M, Short K, Secker GA, Combes A, Schwarz Q, Davidson TL, et al. Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice. Dev Biol. 2012;364(2):89–98.

    Article  CAS  PubMed  Google Scholar 

  23. Hagerling R, Pollmann C, Andreas M, Schmidt C, Nurmi H, Adams RH, et al. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J. 2013;32(5):629–44.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsai A, et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science. 2003;299(5604):247–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bertozzi CC, Hess PR, Kahn ML. Platelets: covert regulators of lymphatic development. Arterioscler Thromb Vasc Biol. 2010a;30(12):2368–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bertozzi CC, Schmaier AA, Mericko P, Hess PR, Zou Z, Chen M, et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood. 2010b;116(4):661–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Carramolino L, Fuentes J, Garcia-Andres C, Azcoitia V, Riethmacher D, Torres M. Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis. Circ Res. 2010;106(7):1197–201.

    Article  CAS  PubMed  Google Scholar 

  28. Suzuki-Inoue K, Inoue O, Ding G, Nishimura S, Hokamura K, Eto K, et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem. 2010;285(32):24494–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Uhrin P, Zaujec J, Breuss JM, Olcaydu D, Chrenek P, Stockinger H, et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood. 2010;115(19):3997–4005.

    Article  CAS  PubMed  Google Scholar 

  30. Debrincat MA, Josefsson EC, James C, Henley KJ, Ellis S, Lebois M, et al. Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival. Blood. 2012;119(24):5850–8.

    Article  CAS  PubMed  Google Scholar 

  31. Hess PR, Rawnsley DR, Jakus Z, Yang Y, Sweet DT, Fu J, et al. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. J Clin Invest. 2014;124(1):273–84.

    Article  CAS  PubMed  Google Scholar 

  32. Norrmen C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, Jaquet M, et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol. 2009;185(3):439–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med. 2004;10(9):974–81.

    Article  CAS  PubMed  Google Scholar 

  34. Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK, Secker GA, et al. GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest. 2015;125(8):2979–94.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Levet S, Ciais D, Merdzhanova G, Mallet C, Zimmers TA, Lee SJ, et al. Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood. 2013;122(4):598–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Murtomaki A, Uh MK, Choi YK, Kitajewski C, Borisenko V, Kitajewski J, et al. Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Development. 2013;140(11):2365–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jurisic G, Maby-El Hajjami H, Karaman S, Ochsenbein AM, Alitalo A, Siddiqui SS, et al. An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ Res. 2012;111(4):426–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 2005;19(3):397–410.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhang G, Brady J, Liang WC, Wu Y, Henkemeyer M, Yan M. EphB4 forward signalling regulates lymphatic valve development. Nat Commun. 2015;6:6625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dellinger M, Hunter R, Bernas M, Gale N, Yancopoulos G, Erickson R, et al. Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice. Dev Biol. 2008;319(2):309–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gale N, Thurston G, Hackett S, Renard R, Wang Q, McClain J, 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;3:411–23.

    Article  CAS  PubMed  Google Scholar 

  42. 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):329–37.

    Article  CAS  PubMed  Google Scholar 

  43. D'Amico G, Korhonen EA, Waltari M, Saharinen P, Laakkonen P, Alitalo K. Loss of endothelial Tie1 receptor impairs lymphatic vessel development-brief report. Arterioscler Thromb Vasc Biol. 2010;30(2):207–9.

    Article  PubMed  Google Scholar 

  44. Qu X, Tompkins K, Batts LE, Puri M, Baldwin HS. Abnormal embryonic lymphatic vessel development in Tie1 hypomorphic mice. Development. 2010;137(8):1285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 2009;17(2):175–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lutter S, Xie S, Tatin F, Makinen T. Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation. J Cell Biol. 2012;197(6):837–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol. 2008;3:367–97.

    Article  CAS  PubMed  Google Scholar 

  48. Saaristo A, Tammela T, Farkkila A, Karkkainen M, Suominen E, Yla-Herttuala S, et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol. 2006;169(3):1080–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. An A, Rockson SG. The potential for molecular treatment strategies in lymphatic disease. Lymphat Res Biol. 2004;2(4):173–81.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

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

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Authors and Affiliations

  1. Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA, USA

    Stanley G. Rockson MD

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  1. Stanley G. Rockson MD
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Correspondence to Stanley G. Rockson MD .

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Editors and Affiliations

  1. Center for the Lymphedema and Vascular Malformations, Division of Vascular Surgery, Department of Surgery, George Washington University, Washington, DC, USA

    Byung-Boong Lee

  2. Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California, USA

    Stanley G. Rockson

  3. La Jolla, California, USA

    John Bergan

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Rockson, S.G. (2018). Embryology of the Lymphatic System and Lymphangiogenesis. In: Lee, BB., Rockson, S., Bergan, J. (eds) Lymphedema. Springer, Cham. https://doi.org/10.1007/978-3-319-52423-8_4

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  • DOI: https://doi.org/10.1007/978-3-319-52423-8_4

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  • Online ISBN: 978-3-319-52423-8

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