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01.01.2014 | Original Paper

Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo

verfasst von: Nadine Jetten, Sanne Verbruggen, Marion J. Gijbels, Mark J. Post, Menno P. J. De Winther, Marjo M. P. C. Donners

Erschienen in: Angiogenesis | Ausgabe 1/2014

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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.

Methods and 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.

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Virmani R et al (2005) Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 25(10):2054–2061PubMedCrossRef

Khurana R et al (2005) Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation 112(12):1813–1824PubMedCrossRef

Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145(3):341–355PubMedCentralPubMedCrossRef

Sluimer JC et al (2008) Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 51(13):1258–1265PubMedCrossRef

Xue L, Greisler HP (2002) Angiogenic effect of fibroblast growth factor-1 and vascular endothelial growth factor and their synergism in a novel in vitro quantitative fibrin-based 3-dimensional angiogenesis system. Surgery 132(2):259–267PubMedCrossRef

Xiong M et al (1998) Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol 153(2):587–598PubMedCrossRef

Schulze-Osthoff K et al (1990) In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol 137(1):85–92PubMed

Pakala R, Watanabe T, Benedict CR (2002) Induction of endothelial cell proliferation by angiogenic factors released by activated monocytes. Cardiovasc Radiat Med 3(2):95–101PubMedCrossRef

Polverini PJ et al (1977) Activated macrophages induce vascular proliferation. Nature 269(5631):804–806PubMedCrossRef

10.

Sunderkotter C et al (1991) Macrophage-derived angiogenesis factors. Pharmacol Ther 51(2):195–216PubMedCrossRef

11.

Gratchev A et al (2006) Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Immunobiology 211(6–8):473–486PubMedCrossRef

12.

Stout RD et al (2005) Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 175(1):342–349PubMed

13.

Wolfs IM, Donners MM, de Winther MP (2011) Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb Haemost 106(5):763–771PubMedCrossRef

14.

Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35PubMedCrossRef

15.

Mantovani A et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686PubMedCrossRef

16.

Mantovani A et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555PubMedCrossRef

17.

Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969PubMedCentralPubMedCrossRef

18.

Kodelja V et al (1997) Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197(5):478–493PubMedCrossRef

19.

Lin EY et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66(23):11238–11246PubMedCrossRef

20.

Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78PubMedCrossRef

21.

Murdoch C et al (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631PubMedCrossRef

22.

Sica A et al (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18(5):349–355PubMedCrossRef

23.

De Palma M et al (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9(6):789–795PubMedCrossRef

24.

Kanters E et al (2004) Hematopoietic NF-kappaB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype. Blood 103(3):934–940PubMedCrossRef

25.

Dirkx AE et al (2006) Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol 80(6):1183–1196PubMedCrossRef

26.

Zhang X et al (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281(23):15694–15700PubMedCentralPubMedCrossRef

27.

He H et al (2012) Endothelial cells provide an instructive niche for the differentiation and functional polarization of M2-like macrophages. Blood 120(15):3152–3162 PubMedCrossRef

28.

Murakami M et al (2011) FGF-dependent regulation of VEGF receptor 2 expression in mice. J Clin Invest 121(7):2668–2678PubMedCentralPubMedCrossRef

29.

Jih YJ et al (2001) Distinct regulation of genes by bFGF and VEGF-A in endothelial cells. Angiogenesis 4(4):313–321PubMedCrossRef

30.

Taraboletti G et al (2002) Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 160(2):673–680PubMedCrossRef

31.

Presta M et al (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16(2):159–178PubMedCrossRef

32.

Anghelina M et al (2004) Monocytes and macrophages form branched cell columns in matrigel: implications for a role in neovascularization. Stem Cells Dev 13(6):665–676PubMedCrossRef

33.

Fantin A et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840PubMedCrossRef

34.

Lamagna C, Aurrand-Lions M, Imhof BA (2006) Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol 80(4):705–713PubMedCrossRef

35.

Rolny C et al (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19(1):31–44PubMedCrossRef

36.

Lewis C, Murdoch C (2005) Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167(3):627–635PubMedCrossRef

37.

Leek RD et al (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625–4629PubMed

38.

Coffelt SB et al (2010) Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 70(13):5270–5280PubMedCrossRef

39.

Porta C et al (2009) Cellular and molecular pathways linking inflammation and cancer. Immunobiology 214(9–10):761–777PubMedCrossRef

40.

De Palma M et al (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211–226PubMedCrossRef

41.

Ribatti D, Levi-Schaffer F, Kovanen PT (2008) Inflammatory angiogenesis in atherogenesis–a double-edged sword. Ann Med 40(8):606–621PubMedCrossRef

42.

Khallou-Laschet J et al (2010) Macrophage plasticity in experimental atherosclerosis. PLoS ONE 5(1):e8852PubMedCentralPubMedCrossRef

43.

Stout RD, Suttles J (2004) Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 76(3):509–513PubMedCentralPubMedCrossRef

Titel: Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo
verfasst von: Nadine Jetten
Sanne Verbruggen
Marion J. Gijbels
Mark J. Post
Menno P. J. De Winther
Marjo M. P. C. Donners
Publikationsdatum: 01.01.2014
Verlag: Springer Netherlands
Erschienen in: Angiogenesis / Ausgabe 1/2014
Print ISSN: 0969-6970
Elektronische ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-013-9381-6

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Abstract

Objective

Methods and results

Conclusions

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