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J Clin Invest. 1997 June 1; 99(11): 2691–2700.
PMCID: PMC508115

Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor.

Abstract

The presence of mast cells near capillary sprouting sites suggests an association between mast cells and angiogenesis. However, the role of mast cells in blood vessel development remains to be defined. In an attempt to elucidate this relationship, we investigated the effect of human mast cells (HMC-1) and their products on human dermal microvascular endothelial cell (HDMEC) tube formation. Coculture of HMC-1 with HDMEC led to a dose-response increase in the network area of vascular tube growth. Moreover, the extent of neovascularization was enhanced greatly when HMC-1 were degranulated in the presence of HDMEC. Further examination using antagonists to various mast cell products revealed a blunted response (73-88% decrease) in the area of vascular tube formation if specific inhibitors of tryptase were present. Tryptase (3 microg/ml) directly added to HDMEC caused a significant augmentation of capillary growth, which was suppressed by specific tryptase inhibitors. Tryptase also directly induced cell proliferation of HDMEC in a dose-dependent fashion (2 pM-2 nM). Our results suggest that mast cells act at sites of new vessel formation by secreting tryptase, which then functions as a potent and previously unrecognized angiogenic factor.

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Selected References

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  • Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994 Apr 22;264(5158):569–571. [PubMed]
  • Findlay JK. Angiogenesis in reproductive tissues. J Endocrinol. 1986 Dec;111(3):357–366. [PubMed]
  • FOLKMAN J, LONG DM, Jr, BECKER FF. Growth and metastasis of tumor in organ culture. Cancer. 1963 Apr;16:453–467. [PubMed]
  • Engerman RL. Pathogenesis of diabetic retinopathy. Diabetes. 1989 Oct;38(10):1203–1206. [PubMed]
  • Meininger CJ, Zetter BR. Mast cells and angiogenesis. Semin Cancer Biol. 1992 Apr;3(2):73–79. [PubMed]
  • Furcht LT. Critical factors controlling angiogenesis: cell products, cell matrix, and growth factors. Lab Invest. 1986 Nov;55(5):505–509. [PubMed]
  • Roche WR. Mast cells and tumour angiogenesis: the tumor-mediated release of an endothelial growth factor from mast cells. Int J Cancer. 1985 Dec 15;36(6):721–728. [PubMed]
  • Gruber BL, Marchese MJ, Kew R. Angiogenic factors stimulate mast-cell migration. Blood. 1995 Oct 1;86(7):2488–2493. [PubMed]
  • Montesano R, Pepper MS, Möhle-Steinlein U, Risau W, Wagner EF, Orci L. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell. 1990 Aug 10;62(3):435–445. [PubMed]
  • Schwartz LB, Lewis RA, Austen KF. Tryptase from human pulmonary mast cells. Purification and characterization. J Biol Chem. 1981 Nov 25;256(22):11939–11943. [PubMed]
  • Schwartz LB. Tryptase: a mast cell serine protease. Methods Enzymol. 1994;244:88–100. [PubMed]
  • Xia HZ, Kepley CL, Sakai K, Chelliah J, Irani AM, Schwartz LB. Quantitation of tryptase, chymase, Fc epsilon RI alpha, and Fc epsilon RI gamma mRNAs in human mast cells and basophils by competitive reverse transcription-polymerase chain reaction. J Immunol. 1995 May 15;154(10):5472–5480. [PubMed]
  • Sakai K, Ren S, Schwartz LB. A novel heparin-dependent processing pathway for human tryptase. Autocatalysis followed by activation with dipeptidyl peptidase I. J Clin Invest. 1996 Feb 15;97(4):988–995. [PMC free article] [PubMed]
  • Caughey GH, Raymond WW, Bacci E, Lombardy RJ, Tidwell RR. Bis(5-amidino-2-benzimidazolyl)methane and related amidines are potent, reversible inhibitors of mast cell tryptases. J Pharmacol Exp Ther. 1993 Feb;264(2):676–682. [PubMed]
  • Sommerhoff CP, Söllner C, Mentele R, Piechottka GP, Auerswald EA, Fritz H. A Kazal-type inhibitor of human mast cell tryptase: isolation from the medical leech Hirudo medicinalis, characterization, and sequence analysis. Biol Chem Hoppe Seyler. 1994 Oct;375(10):685–694. [PubMed]
  • Kubota Y, Kleinman HK, Martin GR, Lawley TJ. Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol. 1988 Oct;107(4):1589–1598. [PMC free article] [PubMed]
  • Meng H, Marchese MJ, Garlick JA, Jelaska A, Korn JH, Gailit J, Clark RA, Gruber BL. Mast cells induce T-cell adhesion to human fibroblasts by regulating intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. J Invest Dermatol. 1995 Dec;105(6):789–796. [PubMed]
  • Butterfield JH, Weiler D, Dewald G, Gleich GJ. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res. 1988;12(4):345–355. [PubMed]
  • Butterfield JH, Weiler DA, Hunt LW, Wynn SR, Roche PC. Purification of tryptase from a human mast cell line. J Leukoc Biol. 1990 May;47(5):409–419. [PubMed]
  • Irani AM, Bradford TR, Kepley CL, Schechter NM, Schwartz LB. Detection of MCT and MCTC types of human mast cells by immunohistochemistry using new monoclonal anti-tryptase and anti-chymase antibodies. J Histochem Cytochem. 1989 Oct;37(10):1509–1515. [PubMed]
  • Montesano R, Orci L. Tumor-promoting phorbol esters induce angiogenesis in vitro. Cell. 1985 Sep;42(2):469–477. [PubMed]
  • Kleinman HK, McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW, Martin GR. Basement membrane complexes with biological activity. Biochemistry. 1986 Jan 28;25(2):312–318. [PubMed]
  • Zimrin AB, Villeponteau B, Maciag T. Models of in vitro angiogenesis: endothelial cell differentiation on fibrin but not matrigel is transcriptionally dependent. Biochem Biophys Res Commun. 1995 Aug 15;213(2):630–638. [PubMed]
  • Alter SC, Metcalfe DD, Bradford TR, Schwartz LB. Regulation of human mast cell tryptase. Effects of enzyme concentration, ionic strength and the structure and negative charge density of polysaccharides. Biochem J. 1987 Dec 15;248(3):821–827. [PubMed]
  • Cowen T, Trigg P, Eady RA. Distribution of mast cells in human dermis: development of a mapping technique. Br J Dermatol. 1979 Jun;100(6):635–640. [PubMed]
  • Kessler DA, Langer RS, Pless NA, Folkman J. Mast cells and tumor angiogenesis. Int J Cancer. 1976 Nov 15;18(5):703–709. [PubMed]
  • Rizzo V, DeFouw DO. Mast cell activation accelerates the normal rate of angiogenesis in the chick chorioallantoic membrane. Microvasc Res. 1996 Nov;52(3):245–257. [PubMed]
  • Azizkhan RG, Azizkhan JC, Zetter BR, Folkman J. Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med. 1980 Oct 1;152(4):931–944. [PMC free article] [PubMed]
  • Jones EW, Heyl T. Naevus sebaceus. A report of 140 cases with special regard to the development of secondary malignant tumours. Br J Dermatol. 1970 Feb;82(2):99–117. [PubMed]
  • Qu Z, Liebler JM, Powers MR, Galey T, Ahmadi P, Huang XN, Ansel JC, Butterfield JH, Planck SR, Rosenbaum JT. Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol. 1995 Sep;147(3):564–573. [PubMed]
  • Pennington DW, Lopez AR, Thomas PS, Peck C, Gold WM. Dog mastocytoma cells produce transforming growth factor beta 1. J Clin Invest. 1992 Jul;90(1):35–41. [PMC free article] [PubMed]
  • Folkman J, Haudenschild C. Angiogenesis in vitro. Nature. 1980 Dec 11;288(5791):551–556. [PubMed]
  • Kubota Y, Kleinman HK, Martin GR, Lawley TJ. Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol. 1988 Oct;107(4):1589–1598. [PMC free article] [PubMed]
  • Grabbe J, Welker P, Möller A, Dippel E, Ashman LK, Czarnetzki BM. Comparative cytokine release from human monocytes, monocyte-derived immature mast cells, and a human mast cell line (HMC-1). J Invest Dermatol. 1994 Oct;103(4):504–508. [PubMed]
  • Nilsson G, Svensson V, Nilsson K. Constitutive and inducible cytokine mRNA expression in the human mast cell line HMC-1. Scand J Immunol. 1995 Jul;42(1):76–81. [PubMed]
  • Irani AM, Gruber BL, Kaufman LD, Kahaleh MB, Schwartz LB. Mast cell changes in scleroderma. Presence of MCT cells in the skin and evidence of mast cell activation. Arthritis Rheum. 1992 Aug;35(8):933–939. [PubMed]
  • Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. [PubMed]
  • Haraguchi M, Miyadera K, Uemura K, Sumizawa T, Furukawa T, Yamada K, Akiyama S, Yamada Y. Angiogenic activity of enzymes. Nature. 1994 Mar 17;368(6468):198–198. [PubMed]
  • Brown JK, Jones CA, Tyler CL, Ruoss SJ, Hartmann T, Caughey GH. Tryptase-induced mitogenesis in airway smooth muscle cells. Potency, mechanisms, and interactions with other mast cell mediators. Chest. 1995 Mar;107(3 Suppl):95S–96S. [PubMed]
  • Hartmann T, Ruoss SJ, Raymond WW, Seuwen K, Caughey GH. Human tryptase as a potent, cell-specific mitogen: role of signaling pathways in synergistic responses. Am J Physiol. 1992 May;262(5 Pt 1):L528–L534. [PubMed]
  • Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J Immunol. 1996 Jan 1;156(1):275–283. [PubMed]
  • Gruber BL, Marchese MJ, Suzuki K, Schwartz LB, Okada Y, Nagase H, Ramamurthy NS. Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation. J Clin Invest. 1989 Nov;84(5):1657–1662. [PMC free article] [PubMed]
  • Stack MS, Johnson DA. Human mast cell tryptase activates single-chain urinary-type plasminogen activator (pro-urokinase). J Biol Chem. 1994 Apr 1;269(13):9416–9419. [PubMed]

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