Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E2

FASEB J. 2011 Jul;25(7):2408-17. doi: 10.1096/fj.10-179473. Epub 2011 Mar 30.


Macrophages contribute to tissue homeostasis in the developing as well as the adult organism. They promote tissue regeneration and remodeling after injury, which requires efficient neoangiogenesis. Signaling pathways activating an angiogenic program in macrophages are still poorly defined. We report that apoptotic cells (ACs), which originate from stressed or damaged tissues, can induce angiogenic properties in primary human macrophages. The signal originating from ACs is the lipid mediator sphingosine-1-phosphate (S1P), which activates S1P1/3 on macrophages to up-regulate cyclooxygenase-2. The formation and liberation of prostaglandin E(2) (PGE(2)) then stimulates migration of endothelial cells. This is demonstrated by using PGE(2) receptor antagonists or a neutralizing PGE(2) antibody in vitro, thereby attenuating endothelial cell migration using a Boyden chamber assay. In vivo, neutralization of PGE(2) from proangiogenic macrophage supernatants blocked vessel formation into Matrigel plugs. In particular, apoptotic cancer cells shifted prostanoid formation in macrophages selectively toward PGE(2) by up-regulating cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES1), while down-regulating the PGE(2)-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) or prostaglandin-D synthase (PGDS). Angiogenic programming of macrophages by ACs, therefore, may control responses to tissue stress such as in tumors, where macrophages support cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Culture Media, Conditioned / metabolism
  • Culture Media, Conditioned / pharmacology
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism*
  • Dinoprostone / pharmacology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • HEK293 Cells
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism
  • Jurkat Cells
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • Prostaglandin-E Synthases
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • U937 Cells


  • Culture Media, Conditioned
  • Lysophospholipids
  • sphingosine 1-phosphate
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Dinoprostone
  • Sphingosine