Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis

Blood. 2010 Nov 25;116(22):4395-403. doi: 10.1182/blood-2010-01-261503. Epub 2010 Jul 12.


Beyond its role in immunity, complement mediates a wide range of functions in the context of morphogenetic or tissue remodeling processes. Angiogenesis is crucial during tissue remodeling in multiple pathologies; however, the knowledge about the regulation of neovascularization by the complement components is scarce. Here we studied the involvement of complement in pathological angiogenesis. Strikingly, we found that mice deficient in the central complement component C3 displayed increased neovascularization in the model of retinopathy of prematurity (ROP) and in the in vivo Matrigel plug assay. In addition, antibody-mediated blockade of C5, treatment with C5aR antagonist, or C5aR deficiency in mice resulted in enhanced pathological retina angiogenesis. While complement did not directly affect angiogenesis-related endothelial cell functions, we found that macrophages mediated the antiangiogenic activity of complement. In particular, C5a-stimulated macrophages were polarized toward an angiogenesis-inhibitory phenotype, including the up-regulated secretion of the antiangiogenic soluble vascular endothelial growth factor receptor-1. Consistently, macrophage depletion in vivo reversed the increased neovascularization associated with C3- or C5aR deficiency. Taken together, complement and in particular the C5a-C5aR axes are potent inhibitors of angiogenesis.

Publication types

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

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Line
  • Complement C3 / genetics
  • Complement C3 / immunology*
  • Complement C5 / immunology*
  • Complement C5a / immunology
  • Gene Deletion
  • Humans
  • Immunity, Innate*
  • Infant, Newborn
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / immunology*
  • Neovascularization, Pathologic / pathology
  • Receptor, Anaphylatoxin C5a / genetics
  • Receptor, Anaphylatoxin C5a / immunology
  • Retina / immunology
  • Retina / pathology*
  • Retinopathy of Prematurity / immunology*
  • Retinopathy of Prematurity / pathology
  • Vascular Endothelial Growth Factors / immunology


  • Complement C3
  • Complement C5
  • Receptor, Anaphylatoxin C5a
  • Vascular Endothelial Growth Factors
  • Complement C5a