, Volume 15, Issue 3, pp 511–519 | Cite as

Dual action of TGF-β induces vascular growth in vivo through recruitment of angiogenic VEGF-producing hematopoietic effector cells

  • Shentong Fang
  • Nalle Pentinmikko
  • Maritta Ilmonen
  • Petri SalvenEmail author
Original Paper


The role of Transforming growth factor β (TGF-β) as a regulator of blood vessel endothelium is complicated and controversial, and the mechanisms by which TGF-β is able to induce angiogenesis in vivo are not well understood. Here we show that TGF-β causes in vivo a massive recruitment of tissue infiltrating hematopoietic cells. Concurrently, TGF-β induces strong vascular endothelial growth factor (VEGF) production in the recruited hematopoietic cells, resulting in activated angiogenesis and vascular remodeling. TGF-β also promoted abnormalities of α-smooth muscle actin-expressing pericytes on angiogenic capillaries. TGF-β-induced angiogenic effect was inhibited by a systemic treatment with VEGF-neutralizing antibodies. When studied in isolated human hematopoietic cells, physiological concentrations of TGF-β stimulated VEGF mRNA and protein expression in a dose- and time-dependent manner. This induction was p38 and p44/p42 mitogen activated kinase dependent. p38 and p44/p42 activation was also observed in vivo in TGF-β–treated angiogenic murine tissues. Taken together, our results provide a dual action mechanism by which TGF-β promotes angiogenesis in vivo via recruitment of paracrine VEGF-expressing hematopoietic effector cells. This mechanism may activate vascular growth and remodeling during inflammatory conditions and tumor growth when TGF-β activity is upregulated.


TGF-β VEGF Angiogenesis Hematopoietic Paracrine 


  1. 1.
    Rifkin DB et al (1993) TGF-beta: structure, function, and formation. Thromb Haemost 70(1):177–179PubMedGoogle Scholar
  2. 2.
    Dickson MC et al (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121(6):1845–1854PubMedGoogle Scholar
  3. 3.
    Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20(9):556–567PubMedCrossRefGoogle Scholar
  4. 4.
    Phillips GD et al (1993) Transforming growth factor beta (TGF-B) stimulation of angiogenesis: an electron microscopic study. J Submicrosc Cytol Pathol 25(2):149–155PubMedGoogle Scholar
  5. 5.
    Roberts AB et al (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83(12):4167–4171PubMedCrossRefGoogle Scholar
  6. 6.
    van Royen N et al (2002) Exogenous application of transforming growth factor beta 1 stimulates arteriogenesis in the peripheral circulation. FASEB J 16(3):432–434PubMedGoogle Scholar
  7. 7.
    Yang EY, Moses HL (1990) Transforming growth factor beta 1-induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J Cell Biol 111(2):731–741PubMedCrossRefGoogle Scholar
  8. 8.
    Ferrari G et al (2009) Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol 219(2):449–458PubMedCrossRefGoogle Scholar
  9. 9.
    Ferrari G et al (2006) VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis. Proc Natl Acad Sci USA 103(46):17260–17265PubMedCrossRefGoogle Scholar
  10. 10.
    Pepper MS et al (1991) Chondrocytes inhibit endothelial sprout formation in vitro: evidence for involvement of a transforming growth factor-beta. J Cell Physiol 146(1):170–179PubMedCrossRefGoogle Scholar
  11. 11.
    Pollman MJ, Naumovski L, Gibbons GH (1999) Vascular cell apoptosis: cell type-specific modulation by transforming growth factor-beta1 in endothelial cells versus smooth muscle cells. Circulation 99(15):2019–2026PubMedCrossRefGoogle Scholar
  12. 12.
    Tsukada T et al (1995) Transforming growth factor beta 1 induces apoptotic cell death in cultured human umbilical vein endothelial cells with down-regulated expression of bcl-2. Biochem Biophys Res Commun 210(3):1076–1082PubMedCrossRefGoogle Scholar
  13. 13.
    Yan Q, Sage EH (1998) Transforming growth factor-beta1 induces apoptotic cell death in cultured retinal endothelial cells but not pericytes: association with decreased expression of p21waf1/cip1. J Cell Biochem 70(1):70–83PubMedCrossRefGoogle Scholar
  14. 14.
    Kim KJ et al (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423):841–844PubMedCrossRefGoogle Scholar
  15. 15.
    Weidner N et al (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143(2):401–409PubMedGoogle Scholar
  16. 16.
    Tischer E et al (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266(18):11947–11954PubMedGoogle Scholar
  17. 17.
    Houck KA et al (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5(12):1806–1814PubMedCrossRefGoogle Scholar
  18. 18.
    Pertovaara L et al (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269(9):6271–6274PubMedGoogle Scholar
  19. 19.
    Jeon SH et al (2007) Mechanisms underlying TGF-beta1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis. J Leukoc Biol 81(2):557–566PubMedCrossRefGoogle Scholar
  20. 20.
    Nam EH, Park SR, Kim PH (2010) TGF-beta1 induces mouse dendritic cells to express VEGF and its receptor (Flt-1) under hypoxic conditions. Exp Mol Med 42(9):606–613PubMedCrossRefGoogle Scholar
  21. 21.
    Salven P et al (1997) Vascular endothelial growth factor in squamous cell head and neck carcinoma: expression and prognostic significance. Mod Pathol 10(11):1128–1133PubMedGoogle Scholar
  22. 22.
    Salven P, Heikkila P, Joensuu H (1997) Enhanced expression of vascular endothelial growth factor in metastatic melanoma. Br J Cancer 76(7):930–934PubMedCrossRefGoogle Scholar
  23. 23.
    Salven P et al (2002) Interleukin-1alpha promotes angiogenesis in vivo via VEGFR-2 pathway by inducing inflammatory cell VEGF synthesis and secretion. FASEB J 16(11):1471–1473PubMedGoogle Scholar
  24. 24.
    Rajantie I et al (2004) Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104(7):2084–2086PubMedCrossRefGoogle Scholar
  25. 25.
    Purhonen S et al (2008) Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 105(18):6620–6625PubMedCrossRefGoogle Scholar
  26. 26.
    Salven P et al (2001) Endotoxins induce and interferon alpha suppresses vascular endothelial growth factor (VEGF) production in human peripheral blood mononuclear cells. FASEB J 15(7):1318–1320PubMedGoogle Scholar
  27. 27.
    Murdoch C et al (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631PubMedCrossRefGoogle Scholar
  28. 28.
    Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796(1):11–18PubMedGoogle Scholar
  29. 29.
    Jain RK, Duda DG (2003) Role of bone marrow-derived cells in tumor angiogenesis and treatment. Cancer Cell 3(6):515–516PubMedCrossRefGoogle Scholar
  30. 30.
    De Palma M, Naldini L (2006) Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis. Biochim Biophys Acta 1766(1):159–166PubMedGoogle Scholar
  31. 31.
    Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103(33):12493–12498PubMedCrossRefGoogle Scholar
  32. 32.
    Shojaei F, Ferrara N (2008) Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res 68(14):5501–5504PubMedCrossRefGoogle Scholar
  33. 33.
    Fang S, Salven P (2011) Stem cells in tumor angiogenesis. J Mol Cell Cardiol 50(2):290–295PubMedCrossRefGoogle Scholar
  34. 34.
    Wartiovaara U et al (1998) Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 80(1):171–175PubMedGoogle Scholar
  35. 35.
    Salven P, Orpana A, Joensuu H (1999) Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res 5(3):487–491PubMedGoogle Scholar
  36. 36.
    Ezaki T et al (2001) Time course of endothelial cell proliferation and microvascular remodeling in chronic inflammation. Am J Pathol 158(6):2043–2055PubMedCrossRefGoogle Scholar
  37. 37.
    Morikawa S et al (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160(3):985–1000PubMedCrossRefGoogle Scholar
  38. 38.
    Teicher BA (2001) Malignant cells, directors of the malignant process: role of transforming growth factor-beta. Cancer Metastasis Rev 20(1–2):133–143PubMedCrossRefGoogle Scholar
  39. 39.
    Assoian RK, Sporn MB (1986) Type beta transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells. J Cell Biol 102(4):1217–1223PubMedCrossRefGoogle Scholar
  40. 40.
    Gaengel K et al (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29(5):630–638PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Shentong Fang
    • 1
  • Nalle Pentinmikko
    • 1
  • Maritta Ilmonen
    • 1
  • Petri Salven
    • 1
    • 2
    Email author
  1. 1.Department of Pathology and Research ProgramsUniversity of HelsinkiHelsinkiFinland
  2. 2.Biomedicum HelsinkiHelsinkiFinland

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