Tissue Macrophages Act as Cellular Chaperones for Vascular Anastomosis Downstream of VEGF-mediated Endothelial Tip Cell Induction

Blood. 2010 Aug 5;116(5):829-40. doi: 10.1182/blood-2009-12-257832. Epub 2010 Apr 19.

Abstract

Blood vessel networks expand in a 2-step process that begins with vessel sprouting and is followed by vessel anastomosis. Vessel sprouting is induced by chemotactic gradients of the vascular endothelial growth factor (VEGF), which stimulates tip cell protrusion. Yet it is not known which factors promote the fusion of neighboring tip cells to add new circuits to the existing vessel network. By combining the analysis of mouse mutants defective in macrophage development or VEGF signaling with live imaging in zebrafish, we now show that macrophages promote tip cell fusion downstream of VEGF-mediated tip cell induction. Macrophages therefore play a hitherto unidentified and unexpected role as vascular fusion cells. Moreover, we show that there are striking molecular similarities between the pro-angiogenic tissue macrophages essential for vascular development and those that promote the angiogenic switch in cancer, including the expression of the cell-surface proteins TIE2 and NRP1. Our findings suggest that tissue macrophages are a target for antiangiogenic therapies, but that they could equally well be exploited to stimulate tissue vascularization in ischemic disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology
  • Endothelial Cells / ultrastructure
  • Endothelium, Vascular / growth & development
  • Female
  • Gene Knock-In Techniques
  • Macrophage Colony-Stimulating Factor / deficiency
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / physiology
  • Macrophages / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / physiology
  • Neuropilin-1 / physiology
  • Proto-Oncogene Proteins / deficiency
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptor, TIE-2
  • Retinal Vessels / growth & development
  • Rhombencephalon / blood supply*
  • Rhombencephalon / embryology
  • Trans-Activators / deficiency
  • Vascular Endothelial Growth Factor A / deficiency
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / physiology*
  • Yolk Sac / cytology
  • Zebrafish / embryology

Substances

  • Proto-Oncogene Proteins
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • proto-oncogene protein Spi-1
  • vascular endothelial growth factor A, mouse
  • Neuropilin-1
  • Macrophage Colony-Stimulating Factor
  • Receptor Protein-Tyrosine Kinases
  • Receptor, TIE-2
  • Tek protein, mouse