Cardiovascular System - Lymphatic Development

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Human embryo (23 mm) mesenteric sac and cisterna chyli
Thoracic and right lymphatic ducts

An important part of the cardiovascular system is the lymphatic vasculature, which functions to both return interstitial fluid (lymph) to the bloodstream and also as part of the immune system. In the embryo, lymphatic development begins at the cardinal vein, where venous endothelial cells differentiate (express Prox1) to form lymphatic endothelial cells that out-pocket and bud to form lymph sacs. During development these lymph sacs remodel to form both the lymphatic space within future nodes, formed by engulfed connective tissue, and the associated afferent and efferent vessel network.

This system was first identified by Aselli G. (1627) in a paper "De Lacteibus sive Lacteis Venis", Quarto Vasorum Mesarai corum Genere novo invento. Milan: Mediolani. Then postulated by Sabin (1902)[1] as venous in origin, it required a recent 2007 lineage tracing study to confirm this theory.[2] Only vertebrates possess a true lymphatic vascular system, with primitive fish possessing a lymphatic-like secondary vascular system that also contains blood. Clinically, important for roles in immune surveillance and oncogenic (cancer) processes.

Historic Embryology
Florence Rena Sabin (1871 - 1953)
lymphatics human embryo CRL 23 mm

Florence Rena Sabin (1871-1953) was an early USA researcher of the embryological development of the lymphatic system. She studied human embryos (from the Carnegie Collection) and used injected ink studies of the pig embryo, A 1912 textbook chapter on "The Development of the Lymphatic System" was one of the earliest reviews of this system.

Immune Links: immune | blood | spleen | thymus | lymphatic | lymph node | Antibody | Med Lecture - Lymphatic Structure | Med Practical | Immune Movies | vaccination | bacterial infection | Abnormalities | Category:Immune
Historic Embryology  
1909 Lymph glands | 1912 Development of the Lymphatic System | 1918 Gray's Lymphatic Images | 1916 Pig Lymphatics | 1919 Chicken Lymphatic | 1921 Spleen | 1922 Pig Stomach Lymphatics | 1932 Cat Pharyngeal Tonsil | Historic Disclaimer

Cardiovascular Links: cardiovascular | Heart Tutorial | Lecture - Early Vascular | Lecture - Heart | Movies | 2016 Cardiac Review | heart | coronary circulation | heart valve | heart rate | Circulation | blood | blood vessel | blood vessel histology | heart histology | Lymphatic | ductus venosus | spleen | Stage 22 | cardiovascular abnormalities | OMIM | 2012 ECHO Meeting | Category:Cardiovascular
Historic Embryology - Cardiovascular 
1902 Vena cava inferior | 1905 Brain Blood Vessels | 1909 Cervical Veins | 1909 Dorsal aorta and umbilical veins | 1912 Heart | 1912 Human Heart | 1914 Earliest Blood-Vessels | 1915 Congenital Cardiac Disease | 1915 Dura Venous Sinuses | 1916 Blood cell origin | 1916 Pars Membranacea Septi | 1919 Lower Limb Arteries | 1921 Human Brain Vascular | 1921 Spleen | 1922 Aortic-Arch System | 1922 Pig Forelimb Arteries | 1922 Chicken Pulmonary | 1923 Head Subcutaneous Plexus | 1923 Ductus Venosus | 1925 Venous Development | 1927 Stage 11 Heart | 1928 Heart Blood Flow | 1935 Aorta | 1935 Venous valves | 1938 Pars Membranacea Septi | 1938 Foramen Ovale | 1939 Atrio-Ventricular Valves | 1940 Vena cava inferior | 1940 Early Hematopoiesis | 1941 Blood Formation | 1942 Truncus and Conus Partitioning | Ziegler Heart Models | 1951 Heart Movie | 1954 Week 9 Heart | 1957 Cranial venous system | 1959 Brain Arterial Anastomoses | Historic Embryology Papers | 2012 ECHO Meeting | 2016 Cardiac Review | Historic Disclaimer

Some Recent Findings

  • MAFB Modulates the Maturation of Lymphatic Vascular Networks in Mice[3] "Lymphatic vessels play key roles in tissue fluid homeostasis, immune cell trafficking and in diverse disease settings. Lymphangiogenesis requires lymphatic endothelial cell (LEC) differentiation, proliferation, migration and co-ordinated network formation, yet the transcriptional regulators underpinning these processes remain to be fully understood. The transcription factor MAFB was recently identified as essential for lymphangiogenesis in zebrafish and in cultured human LECs. MAFB is activated in response to VEGFC-VEGFR3 signalling and acts as a downstream effector. However, it remains unclear if the role of MAFB in lymphatic development is conserved in the mammalian embryo. We generated a Mafb loss-of-function mouse using CRISPR/Cas9 gene editing. Mafb mutant mice presented with perinatal lethality associated with cyanosis. Mafb mutant lymphatics were normal during initial LEC differentiation and sprouting. However, we identify a role for MAFB in modifying lymphatic network morphogenesis in the developing dermis, as well as developing and postnatal diaphragm. Furthermore, mutant vessels displayed excessive smooth muscle cell coverage, suggestive of a defect in the maturation of lymphatic networks."
  • Paraxial Mesoderm Is the Major Source of Lymphatic Endothelium[4] " Endothelial cells (ECs), which line blood and lymphatic vessels, are generally described to come from the lateral plate mesoderm despite experimental evidence for a broader source of origin, including the paraxial mesoderm (PXM). Current dogma suggests that following specification from mesoderm, local environmental cues establish the distinct molecular and functional characteristics of ECs in different vascular beds. Here we present evidence to challenge this view, showing that lymphatic EC fate is imprinted during transition through the PXM lineage. We show that PXM-derived cells form the lymphatic endothelium of multiple organs and tissues, with a more restricted contribution to blood vessel endothelium. By deleting Prox1 specifically in PXM-derived cells, we show that this lineage is indispensable for lymphatic vessel development. Collectively, our data establish lineage history as a critical determinant of EC specialization, a finding with broad implications for our understanding of vascular development and heterogeneity."
  • Review - Key molecules in lymphatic development, function, and identification[5] "While both blood and lymphatic vessels transport fluids and thus share many similarities, they also show functional and structural differences, which can be used to differentiate them. Specific visualization of lymphatic vessels has historically been and still is a pivot point in lymphatic research. Many of the proteins that are investigated by molecular biologists in lymphatic research have been defined as marker molecules, i.e. to visualize and distinguish lymphatic endothelial cells (LECs) from other cell types, most notably from blood vascular endothelial cells (BECs) and cells of the hematopoietic lineage. Among the factors that drive the developmental differentiation of lymphatic structures from venous endothelium, Prospero homeobox protein 1 (PROX1) is the master transcriptional regulator. PROX1 maintains lymphatic identity also in the adult organism and thus is a universal LEC marker. Vascular endothelial growth factor receptor-3 (VEGFR-3) is the major tyrosine kinase receptor that drives LEC proliferation and migration. The major activator for VEGFR-3 is vascular endothelial growth factor-C (VEGF-C). However, before VEGF-C can signal, it needs to be proteolytically activated by an extracellular protein complex comprised of Collagen and calcium binding EGF domains 1 (CCBE1) protein and the protease A disintegrin and metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3)."
More recent papers  
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Search term: Lymphatic Development | Lymphatic Vessel Development

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Development of the mammalian lymphatic vasculature[6] "The two vascular systems of our body are the blood and lymphatic vasculature. Our understanding of the cellular and molecular processes controlling the development of the lymphatic vasculature has progressed significantly in the last decade. In mammals, this is a stepwise process that starts in the embryonic veins, where lymphatic EC (LEC) progenitors are initially specified. The differentiation and maturation of these progenitors continues as they bud from the veins to produce scattered primitive lymph sacs, from which most of the lymphatic vasculature is derived. Here, we summarize our current understanding of the key steps leading to the formation of a functional lymphatic vasculature."

  • prox1b Activity is essential in zebrafish lymphangiogenesis[7] "The lymphatic vascular system, draining interstitial fluids from most tissues and organs, exerts crucial functions in several physiological and pathological processes. Lymphatic system development depends on Prox1, the first marker to be expressed in the endothelial cells of the cardinal vein from where lymph vessels originate."
  • Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature[2] "These studies, together with the analysis of Runx1-mutant embryos lacking definitive hematopoiesis, conclusively determined that from venous-derived lymph sacs, lymphatic endothelial cells sprouted, proliferated, and migrated to give rise to the entire lymphatic vasculature, and that hematopoietic cells did not contribute to the developing lymph sacs. We conclude that the mammalian lymphatic system has a solely venous origin."
  • The lymphatic vasculature: recent progress and paradigms[8] "The field of lymphatic research has been recently invigorated by the identification of genes and mechanisms that control various aspects of lymphatic development. We are beginning to understand how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner. The generation of genetically engineered mice with defects in different steps of the lymphangiogenic program has provided models that are increasing our understanding of the lymphatic system in health and disease."

Lymphatic Vessels

Lymph capillary
  1. Lymph capillaries - begin as blind-ending tubes in connective tissue, larger than blood capillaries, very irregularly shaped.
  2. Lymph collecting vessels - larger and form valves, morphology similar to lymph capillaries.
  3. Lymph ducts - 1 or 2 layers of smooth muscle cells in wall.
(Remember the anatomy acronym NAVL = Nerve, Artery, Vein and Lymph)

Lymphatic Capillaries

  • single-cell layer of overlapping endothelial cells
    • lack a basement membrane
    • lack smooth muscle cells or pericytes (pre-collecting and collecting trunks contain both)
  • linked by discontinuous endothelial cell-cell junctions (button-like).
  • junctions open in response to increased interstitial fluid pressure.

Lymphatic microvasculature model.jpg

Lymphatic microvasculature model[9]

Lymphatic Vessel Development

Lymphatic vessel formation model.jpg

Tunneling model of lymphatic vessel formation.

The model shown here is from a recent paper[10] and is based on ultrastructural observations performed in in vitro and in vivo models of lymphangiogenesis. Lymphatic endothelial cells (LEC) display tight junctions and interdigitations, and are connected to the surrounding collagen fibers by anchoring filaments.

Note that this postnatal model may differ from developmental lymphatic vessel development.

  • A - LEC alignment. Elongated LEC migrate and extend long cytoplasmic protrusions.

  • B - Vacuolization and matrix degradation. The continuity of LEC lining is mediated by interdigitations (i). Vesicle invaginations lead to the formation of intracellular vacuoles (v) in the cytoplasm and in protrusions. Matrix degradation (d) occurs intracellularly and extracellularly generating space between cells.

  • C - Luminogenesis. The lumen (lu) is formed de novo in the intercellular space. The intracellular vacuoles coalesce (cv) and likely fuse with the cytoplasmic membrane to increase the lumen.

Lymphatic Vessel Contraction

Lymphatic vessels undergo spontaneous rhythmic contractions which aid lymph flow. This is most easily demonstrated in models based upon mesentry lymphatics of the gastrointestinal tract. Contractile activity is regulated by physical factors (transmural pressure) and neurological (alpha-adrenergic, histamine, bradykinin) acting on lymphatic smooth muscle. Contractility and receptor expression may also be different in different parts of the lymphatic system.

Alpha-adrenergic - alpha 1- and not alpha 2-adrenoceptors.

Histamine - lymphatic smooth muscle via stimulation of H(1) (and in some vessels H(2)) receptors.

Bradykinin - chronotropic but not inotropic effects on lymphatic pump activity via stimulation of B1 receptors.

Lymphatic vasculature 01.jpg

Lymphatic Vasculature Organization[11]

Molecular Development

Angiopoietins (Ang1–Ang4)

Notch probably mediates choice of fate between arterial and venous.

Prox1 Prospero-related Homeobox 1 - expressed in a subpopulation of blood endothelial cells that then generate, by both budding and sprouting, cells of the lymphatic vascular system. Triggers the molecular program leading to the formation of the lymphatic system. (OMIM - PROSPERO-RELATED HOMEOBOX 1; PROX1)

Tie (Tie1 and Tie2) tyrosine kinase receptors.

Vascular endothelial growth factor (VEGF) family of proteins and angiopoietin/Tie, Notch, and ephrin/Eph pathways play major roles in eary vessel development. (VEGFR-3)





Dysplasia of childhood form lymphatic capillaries or collectors, which form fluid-filled cysts.

  • lymphatic spaces lined by endothelium
  • smooth muscle fascicles in the septa between the lymphatic spaces
  • lymphoid aggregates in the delicate collagenous stroma


  1. Sabin FR. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig (1902) Amer. J Anat. 1(3): 367-389.
  2. 2.0 2.1 Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM & Oliver G. (2007). Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. , 21, 2422-32. PMID: 17908929 DOI.
  3. Rondon-Galeano M, Skoczylas R, Bower NI, Simons C, Gordon E, Francois M, Koltowska K & Hogan BM. (2020). MAFB modulates the maturation of lymphatic vascular networks in mice. Dev. Dyn. , , . PMID: 32525258 DOI.
  4. Stone OA & Stainier DYR. (2019). Paraxial Mesoderm Is the Major Source of Lymphatic Endothelium. Dev. Cell , , . PMID: 31130354 DOI.
  5. Jha SK, Rauniyar K & Jeltsch M. (2018). Key molecules in lymphatic development, function, and identification. Ann. Anat. , 219, 25-34. PMID: 29842991 DOI.
  6. Yang Y & Oliver G. (2014). Development of the mammalian lymphatic vasculature. J. Clin. Invest. , 124, 888-97. PMID: 24590273 DOI.
  7. Del Giacco L, Pistocchi A & Ghilardi A. (2010). prox1b Activity is essential in zebrafish lymphangiogenesis. PLoS ONE , 5, e13170. PMID: 20976189 DOI.
  8. Oliver G & Alitalo K. (2005). The lymphatic vasculature: recent progress and paradigms. Annu. Rev. Cell Dev. Biol. , 21, 457-83. PMID: 16212503 DOI.
  9. Pepper MS & Skobe M. (2003). Lymphatic endothelium: morphological, molecular and functional properties. J. Cell Biol. , 163, 209-13. PMID: 14581448 DOI.
  10. Detry B, Bruyère F, Erpicum C, Paupert J, Lamaye F, Maillard C, Lenoir B, Foidart JM, Thiry M & Noël A. (2011). Digging deeper into lymphatic vessel formation in vitro and in vivo. BMC Cell Biol. , 12, 29. PMID: 21702933 DOI.
  11. Schulte-Merker S, Sabine A & Petrova TV. (2011). Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol. , 193, 607-18. PMID: 21576390 DOI.



Oliver G & Srinivasan RS. (2008). Lymphatic vasculature development: current concepts. Ann. N. Y. Acad. Sci. , 1131, 75-81. PMID: 18519960 DOI.

Bellini C, Boccardo F, Bonioli E & Campisi C. (2006). Lymphodynamics in the fetus and newborn. Lymphology , 39, 110-7. PMID: 17036631

Oliver G & Alitalo K. (2005). The lymphatic vasculature: recent progress and paradigms. Annu. Rev. Cell Dev. Biol. , 21, 457-83. PMID: 16212503 DOI.

Takahashi M, Yoshimoto T & Kubo H. (2004). Molecular mechanisms of lymphangiogenesis. Int. J. Hematol. , 80, 29-34. PMID: 15293565

Oliver G. (2004). Lymphatic vasculature development. Nat. Rev. Immunol. , 4, 35-45. PMID: 14704766 DOI.

Oliver G & Harvey N. (2002). A stepwise model of the development of lymphatic vasculature. Ann. N. Y. Acad. Sci. , 979, 159-65; discussion 188-96. PMID: 12543725


Gancz D, Perlmoter G & Yaniv K. (2019). Formation and Growth of Cardiac Lymphatics during Embryonic Development, Heart Regeneration, and Disease. Cold Spring Harb Perspect Biol , , . PMID: 31818858 DOI.

Johnson NC, Dillard ME, Baluk P, McDonald DM, Harvey NL, Frase SL & Oliver G. (2008). Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev. , 22, 3282-91. PMID: 19056883 DOI.

Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM & Oliver G. (2007). Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. , 21, 2422-32. PMID: 17908929 DOI.

Bäckhed F, Crawford PA, O'Donnell D & Gordon JI. (2007). Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc. Natl. Acad. Sci. U.S.A. , 104, 606-11. PMID: 17202268 DOI.

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, 576-84. PMID: 16291864 DOI.

Karpanen T, Wirzenius M, Mäkinen T, Veikkola T, Haisma HJ, Achen MG, Stacker SA, Pytowski B, Ylä-Herttuala S & Alitalo K. (2006). Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am. J. Pathol. , 169, 708-18. PMID: 16877368 DOI.

Oliver G & Detmar M. (2002). The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. , 16, 773-83. PMID: 11937485 DOI.

Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity Nicole C. Johnson, Miriam E. Dillard, Peter Baluk, Donald M. McDonald, Natasha L. Harvey, Sharon L. Frase, and Guillermo Oliver Genes Dev. 2008;22 3282-3291

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