VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells

Cell Rep. 2021 Jun 15;35(11):109255. doi: 10.1016/j.celrep.2021.109255.


The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell cycle stages, we show that venous and lymphatic precursors sprout from the cardinal vein exclusively in G1 and reveal that cell-cycle arrest is induced in these ECs by overexpression of p53 and the cyclin-dependent kinase (CDK) inhibitors p27 and p21. We further demonstrate that, in vivo, forcing G1 cell-cycle arrest results in enhanced vascular sprouting. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as a direct inducer of cell-cycle arrest in ECs and characterize the cascade of events that render "sprouting-competent" ECs. Overall, our results uncover a mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell cycle inhibitors in pathological angiogenesis and lymphangiogenesis.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Cycle Checkpoints* / drug effects
  • Cell Differentiation
  • Endothelial Cells* / cytology
  • Endothelial Cells* / drug effects
  • Endothelial Cells* / metabolism
  • G1 Phase
  • Lymphatic Vessels* / cytology
  • MAP Kinase Signaling System
  • Neovascularization, Physiologic* / drug effects
  • Roscovitine / pharmacology
  • Vascular Endothelial Growth Factor C* / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism
  • Veins* / cytology
  • Zebrafish
  • Zebrafish Proteins* / metabolism


  • Roscovitine
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • Zebrafish Proteins
  • flt4 protein, zebrafish