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Cited by 1,006Lymphatic System and DiseasesLymphatic Disorders and TreatmentsBarrier Structure and Function Studies

Functionally specialized junctions between endothelial cells of lymphatic vessels

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Baluk, Peter, Fuxe, Jonas, Hashizume, Hiroya, Romano, Talia, Lashnits, Erin, Butz, Stefan, Vestweber, Dietmar, Corada, Monica +3 more·2007·The Journal of Experimental Medicine
DOI 10.1084/jem.20062596PMC PMC2118470
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Abstract

Recirculation of fluid and cells through lymphatic vessels plays a key role in normal tissue homeostasis, inflammatory diseases, and cancer. Despite recent advances in understanding lymphatic function (Alitalo, K., T. Tammela, and T.V. Petrova. 2005. Nature. 438:946–953), the cellular features responsible for entry of fluid and cells into lymphatics are incompletely understood. We report the presence of novel junctions between endothelial cells of initial lymphatics at likely sites of fluid entry. Overlapping flaps at borders of oak leaf–shaped endothelial cells of initial lymphatics lacked junctions at the tip but were anchored on the sides by discontinuous button-like junctions (buttons) that differed from conventional, continuous, zipper-like junctions (zippers) in collecting lymphatics and blood vessels. However, both buttons and zippers were composed of vascular endothelial cadherin (VE-cadherin) and tight junction–associated proteins, including occludin, claudin-5, zonula occludens–1, junctional adhesion molecule–A, and endothelial cell–selective adhesion molecule. In C57BL/6 mice, VE-cadherin was required for maintenance of junctional integrity, but platelet/endothelial cell adhesion molecule–1 was not. Growing tips of lymphatic sprouts had zippers, not buttons, suggesting that buttons are specialized junctions rather than immature ones. Our findings suggest that fluid enters throughout initial lymphatics via openings between buttons, which open and close without disrupting junctional integrity, but most leukocytes enter the proximal half of initial lymphatics.

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  • The total surface area of lymphatic capillaries is substantial, and their walls are composed of specialized LEC junctions that facilitate reabsorption and prevent back leak of interstitial fluid and protein.

    “The total surface area of lymphatic capillaries is substantial, and their walls are composed of specialized LEC junctions that facilitate reabsorption and prevent back leak of interstitial fluid and protein (13).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [13]

    The Abstract and Discussion describe specialized button-like junctions in initial lymphatics and propose that openings between them permit fluid entry; the Discussion also describes the flaps as permitting unidirectional flow. Our copy does not establish that lymphatic capillaries have a substantial total surface area, or demonstrate that these junctions prevent back-leak of interstitial fluid and protein. The Discussion explicitly says that the proposed sites of fluid entry have not been directly visualized. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Collecting LVs have a continuous basement membrane and zipper-like LEC junctions composed of continuous borders of adherens and tight junction proteins.

    “In contrast, collecting LVs have a continuous basement membrane and zipper-like LEC junctions (13) composed of continuous borders of adherens and tight junction proteins.”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [13]

    The Results sections on buttons and junctional proteins report continuous zipper-like junctions in collecting lymphatics, with VE-cadherin and continuously distributed tight-junction proteins. Our copy does not state that collecting lymphatic vessels have a continuous basement membrane; its mention of basement membrane is in a reference title. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Lymphatic capillaries have a sparse or discontinuous basement membrane, with button-like LEC-LEC junctions characterized by punctate expression of adherens and tight junction proteins.

    “Lymphatic capillaries have a sparse or discontinuous basement membrane, with button-like LEC-LEC junctions (13) characterized by punctate expression of adherens and tight junction proteins.”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [13]

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Authors
Baluk, P., Fuxe, J., Hashizume, H., Romano, T., Lashnits, E., Butz, S., Vestweber, D., Corada, M., Molendini, C., Dejana, E., & McDonald, D. M.
Affiliations
  • 1Cardiovascular Research Institute
  • University of California, San Francisco (US)
  • University of Münster (DE)
  • IFOM (IT)
  • University of Milan (IT)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2007-09-10
Volume
204
Issue
10
Pages
2349-2362
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20062596
PMC
PMC2118470
OpenAlex
W2158659385
Cited by
1,006
References
2
Citations by year
2026: 41 · 2025: 52 · 2024: 67 · 2023: 66 · 2022: 70 · 2021: 86 · 2020: 55 · 2019: 65 · 2018: 57 · 2017: 46 · 2016: 48 · 2015: 53 · 2014: 56 · 2013: 57 · 2012: 49
FWCI
17.88
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
Funders
  • National Heart, Lung, and Blood Institute (R01HL059157, HL 24136, HL 59157, P01HL024136)
  • National Cancer Institute (CA-82923, R01CA082923)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
lymphatic endothelial cells, VE-cadherin, tight junctions, occludin, claudin-5, zonula occludens-1, JAM-A, E-selectin, initial lymphatics
MeSH terms
Animals, Cell Movement, Lymphocytes, Mice, Inbred C57BL, Cadherins, Platelet Endothelial Cell Adhesion Molecule-1, Lymphatic Vessels, Endothelial Cells, Mice

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