title: Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo.
abstract: OBJECTIVE
  Macrophages show extreme heterogeneity and different subsets have been characterized by their activation route and their function. For instance, macrophage subsets are distinct by acting differently under pathophysiological conditions such as inflammation and cancer. Macrophages also contribute to angiogenesis, but the role of various specific subsets in angiogenesis has not been thoroughly investigated.
  
  
  RESULTS
  Matrigel supplemented with macrophage subsets [induced by IFNγ (M1), IL-4 (M2a) or IL-10 (M2c)] was injected subcutaneously in C57BL/6 J mice and analyzed by CD31 staining after 14 days. Increased numbers of endothelial cells and tubular structures were observed in M2-enriched plugs compared to control and other subsets. Additionally, more tubular structures formed in vitro in the presence of M2 macrophages or their conditioned medium. To identify a mechanism for the pro-angiogenic effect, gene expression of angiogenic growth factors was analyzed. Induced expression of basic fibroblast growth factor (Fgf2), insulin-like growth factor-1 (Igf1), chemokine (C-C motif) ligand 2 (Ccl2) and placental growth factor (Pgf) was observed in M2 macrophages. Using a blocking antibody of PlGF to inhibit M2c induced angiogenesis resulted in mildly reduced (40 %) tube formation whereas neutralization of FGF-2 (M2a) signaling by sFGFR1-IIIc affected tube formation by nearly 75 %.
  
  
  CONCLUSIONS
  These results indicate that macrophages polarized towards an M2 phenotype have a higher angiogenic potential compared to other subsets. Furthermore, we propose FGF signaling for M2a- and PlGF signaling for M2c-induced angiogenesis as possible working mechanisms, yet, further research should elucidate the exact mechanism for M2-induced angiogenesis.
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jetten
authors.forename: Sanne
authors.initials: S
authors.lastname: Verbruggen
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Post
authors.forename: Menno P J
authors.initials: MP
authors.lastname: De Winther
authors.forename: Marjo M P C
authors.initials: MM
authors.lastname: Donners
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D043925:Angiogenesis Inducing Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; C519530:insulin-like growth factor-1, mouse; D016222:Fibroblast Growth Factor 2; D000072483:Placenta Growth Factor; D007334:Insulin-Like Growth Factor I