Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms

Nat Commun. 2018 Apr 3;9(1):1296. doi: 10.1038/s41467-018-03692-0.


Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+ cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3- LECs non-cell-autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+ LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / metabolism
  • Female
  • Gene Deletion
  • Humans
  • Hyperplasia / metabolism
  • Image Processing, Computer-Assisted
  • Lymphangiogenesis
  • Lymphatic Vessels / metabolism*
  • Mice
  • Phenotype
  • RNA Interference
  • Signal Transduction
  • Skin / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*


  • FLT4 protein, human
  • Vascular Endothelial Growth Factor Receptor-3