Nonvenous origin of dermal lymphatic vasculature

Circ Res. 2015 May 8;116(10):1649-54. doi: 10.1161/CIRCRESAHA.116.306170. Epub 2015 Mar 3.


Rationale: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals.

Objective: We aimed to clarify the origin of the murine dermal lymphatic vasculature.

Methods and results: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis.

Conclusions: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.

Keywords: developmental biology; endothelial cells; endothelial progenitor cells; lymphangiogenesis; lymphatic vessels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation
  • Cell Lineage*
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • Endothelial Progenitor Cells / cytology*
  • Endothelial Progenitor Cells / metabolism
  • Endothelium, Lymphatic / cytology*
  • Endothelium, Lymphatic / metabolism
  • Genes, Reporter
  • Gestational Age
  • Homeodomain Proteins / genetics
  • Lymphangiogenesis*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Receptor, TIE-2 / metabolism
  • Skin / blood supply*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Veins / cytology
  • Veins / metabolism


  • Biomarkers
  • Homeodomain Proteins
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • Receptor, TIE-2
  • Tek protein, mouse
  • Vascular Endothelial Growth Factor Receptor-3