Hif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish

Nat Commun. 2017 May 19;8:15492. doi: 10.1038/ncomms15492.

Abstract

Macrophages are known to interact with endothelial cells during developmental and pathological angiogenesis but the molecular mechanisms modulating these interactions remain unclear. Here, we show a role for the Hif-1α transcription factor in this cellular communication. We generated hif-1aa;hif-1ab double mutants in zebrafish, hereafter referred to as hif-1α mutants, and find that they exhibit impaired macrophage mobilization from the aorta-gonad-mesonephros (AGM) region as well as angiogenic defects and defective vascular repair. Importantly, macrophage ablation is sufficient to recapitulate the vascular phenotypes observed in hif-1α mutants, revealing for the first time a macrophage-dependent angiogenic process during development. Further substantiating our observations of vascular repair, we find that most macrophages closely associated with ruptured blood vessels are Tnfα-positive, a key feature of classically activated macrophages. Altogether, our data provide genetic evidence that Hif-1α regulates interactions between macrophages and endothelial cells starting with the mobilization of macrophages from the AGM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Blood Vessels / embryology*
  • Endothelial Cells / cytology*
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Macrophages / cytology*
  • Microscopy, Confocal
  • Mutation
  • Neovascularization, Pathologic / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Oxygen / chemistry
  • Phenotype
  • Sample Size
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism*
  • Zebrafish / embryology

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A
  • Oxygen