ZFIN ID: ZDB-PUB-100820-10
Identification and functional analysis of endothelial tip cell-enriched genes
Del Toro, R., Prahst, C., Mathivet, T., Siegfried, G., Kaminker, J.S., Larrivee, B., Breant, C., Duarte, A., Takakura, N., Fukamizu, A., Penninger, J., and Eichmann, A.
Date: 2010
Source: Blood   116(19): 4025-4033 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Adipokines
  • Animals
  • Capillaries/cytology
  • Capillaries/growth & development
  • Capillaries/metabolism
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism
  • Endothelial Cells/cytology
  • Endothelial Cells/drug effects
  • Endothelial Cells/metabolism*
  • Extracellular Matrix/metabolism
  • Gene Expression Profiling
  • Haploinsufficiency
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins/deficiency
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Membrane Proteins/deficiency
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multigene Family
  • Neovascularization, Physiologic/genetics*
  • Oligonucleotide Array Sequence Analysis
  • Receptors, G-Protein-Coupled/deficiency
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism
  • Retinal Vessels/cytology
  • Retinal Vessels/growth & development
  • Retinal Vessels/metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases/metabolism
  • Vascular Endothelial Growth Factor A/pharmacology
  • Zebrafish
PubMed: 20705756 Full text @ Blood
Sprouting of developing blood vessels is mediated by specialized motile endothelial cells localized at the tips of growing capillaries. Following behind the tip cells, endothelial stalk cells form the capillary lumen and proliferate. Expression of the Notch ligand Delta-like4 (Dll4) in tip cells suppresses tip cell fate in neighboring stalk cells via Notch signaling. In dll4(+/-) mouse mutants, most retinal endothelial cells display morphological features of tip cells. We hypothesized that these mouse mutants could be used to isolate tip cells and to so determine their genetic repertoire. Using transcriptome analysis of retinal endothelial cells isolated from dll4(+/-) and wild type mice, we identified three clusters of tip cell-enriched genes, encoding extracellular matrix degrading enzymes, basement membrane components and secreted molecules. Secreted molecules ESM-1, angiopoietin 2 and apelin bind to cognate receptors on endothelial stalk cells. Knockout mice and zebrafish morpholino knockdown of apelin showed delayed angiogenesis and reduced proliferation of stalk cells expressing the apelin receptor APJ. Thus, tip cells may regulate angiogenesis via matrix remodeling, production of basement membrane and release of secreted molecules, some of which regulate stalk cell behavior.