VE-Cadherin Is Required for Lymphatic Valve Formation and Maintenance

Cell Rep. 2019 Aug 27;28(9):2397-2412.e4. doi: 10.1016/j.celrep.2019.07.072.


The lymphatic vasculature requires intraluminal valves to maintain forward lymph flow. Lymphatic valves form and are constantly maintained by oscillatory fluid flow throughout life, yet the earliest steps of how lymphatic endothelial cells are able to respond to fluid shear stress remain unknown. Here, we show that the adherens junction protein VE-cadherin is required for the upregulation of valve-specific transcription factors. Conditional deletion of VE-cadherin in vivo prevented valve formation in the embryo and caused postnatal regression of nearly all lymphatic valves in multiple tissues. Since VE-cadherin is known to signal through β-catenin and the VEGFR/AKT pathway, each pathway was probed. Expression of a constitutively active β-catenin mutant or direct pharmacologic activation of AKT in vivo significantly rescued valve regression in the VE-cadherin-deficient lymphatic vessels. In conclusion, VE-cadherin-dependent signaling is required for lymphatic valve formation and maintenance and therapies to augment downstream pathways hold potential to treat lymphedema in patients.

Keywords: Akt; mechanotransduction; shear stress; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cells, Cultured
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Lymphatic Vessels / embryology
  • Lymphatic Vessels / metabolism*
  • Lymphatic Vessels / physiology
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • beta Catenin / metabolism


  • Antigens, CD
  • Cadherins
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Tumor Suppressor Proteins
  • beta Catenin
  • cadherin 5
  • mesenchyme fork head 1 protein
  • prospero-related homeobox 1 protein
  • Receptors, Vascular Endothelial Growth Factor
  • Proto-Oncogene Proteins c-akt