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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- Alter S. C., Metcalfe D. D., Bradford T. R., Schwartz L. B. 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. doi: 10.1042/bj2480821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Azizkhan R. G., Azizkhan J. C., Zetter B. R., Folkman J. Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med. 1980 Oct 1;152(4):931–944. doi: 10.1084/jem.152.4.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brooks P. C., Clark R. A., Cheresh D. A. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994 Apr 22;264(5158):569–571. doi: 10.1126/science.7512751. [DOI] [PubMed] [Google Scholar]
- Brown J. K., Jones C. A., Tyler C. L., Ruoss S. J., Hartmann T., Caughey G. H. 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. doi: 10.1378/chest.107.3_supplement.95s. [DOI] [PubMed] [Google Scholar]
- Butterfield J. H., Weiler D. A., Hunt L. W., Wynn S. R., Roche P. C. Purification of tryptase from a human mast cell line. J Leukoc Biol. 1990 May;47(5):409–419. doi: 10.1002/jlb.47.5.409. [DOI] [PubMed] [Google Scholar]
- Butterfield J. H., Weiler D., Dewald G., Gleich G. J. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res. 1988;12(4):345–355. doi: 10.1016/0145-2126(88)90050-1. [DOI] [PubMed] [Google Scholar]
- Cairns J. A., Walls A. F. 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] [Google Scholar]
- Caughey G. H., Raymond W. W., Bacci E., Lombardy R. J., Tidwell R. R. 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] [Google Scholar]
- Cowen T., Trigg P., Eady R. A. Distribution of mast cells in human dermis: development of a mapping technique. Br J Dermatol. 1979 Jun;100(6):635–640. doi: 10.1111/j.1365-2133.1979.tb08066.x. [DOI] [PubMed] [Google Scholar]
- Engerman R. L. Pathogenesis of diabetic retinopathy. Diabetes. 1989 Oct;38(10):1203–1206. doi: 10.2337/diab.38.10.1203. [DOI] [PubMed] [Google Scholar]
- FOLKMAN J., LONG D. M., Jr, BECKER F. F. Growth and metastasis of tumor in organ culture. Cancer. 1963 Apr;16:453–467. doi: 10.1002/1097-0142(196304)16:4<453::aid-cncr2820160407>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
- Findlay J. K. Angiogenesis in reproductive tissues. J Endocrinol. 1986 Dec;111(3):357–366. doi: 10.1677/joe.0.1110357. [DOI] [PubMed] [Google Scholar]
- Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. doi: 10.1038/nm0195-27. [DOI] [PubMed] [Google Scholar]
- Folkman J., Haudenschild C. Angiogenesis in vitro. Nature. 1980 Dec 11;288(5791):551–556. doi: 10.1038/288551a0. [DOI] [PubMed] [Google Scholar]
- Furcht L. T. Critical factors controlling angiogenesis: cell products, cell matrix, and growth factors. Lab Invest. 1986 Nov;55(5):505–509. [PubMed] [Google Scholar]
- Grabbe J., Welker P., Möller A., Dippel E., Ashman L. K., Czarnetzki B. M. 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. doi: 10.1111/1523-1747.ep12395649. [DOI] [PubMed] [Google Scholar]
- Gruber B. L., Marchese M. J., Kew R. Angiogenic factors stimulate mast-cell migration. Blood. 1995 Oct 1;86(7):2488–2493. [PubMed] [Google Scholar]
- Gruber B. L., Marchese M. J., Suzuki K., Schwartz L. B., Okada Y., Nagase H., Ramamurthy N. S. Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation. J Clin Invest. 1989 Nov;84(5):1657–1662. doi: 10.1172/JCI114344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. doi: 10.1038/368198a0. [DOI] [PubMed] [Google Scholar]
- Hartmann T., Ruoss S. J., Raymond W. W., Seuwen K., Caughey G. H. 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. doi: 10.1152/ajplung.1992.262.5.L528. [DOI] [PubMed] [Google Scholar]
- Irani A. M., Bradford T. R., Kepley C. L., Schechter N. M., Schwartz L. B. 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. doi: 10.1177/37.10.2674273. [DOI] [PubMed] [Google Scholar]
- Irani A. M., Gruber B. L., Kaufman L. D., Kahaleh M. B., Schwartz L. B. 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. doi: 10.1002/art.1780350813. [DOI] [PubMed] [Google Scholar]
- Jones E. W., 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. doi: 10.1111/j.1365-2133.1970.tb15000.x. [DOI] [PubMed] [Google Scholar]
- Kessler D. A., Langer R. S., Pless N. A., Folkman J. Mast cells and tumor angiogenesis. Int J Cancer. 1976 Nov 15;18(5):703–709. doi: 10.1002/ijc.2910180520. [DOI] [PubMed] [Google Scholar]
- Kleinman H. K., McGarvey M. L., Hassell J. R., Star V. L., Cannon F. B., Laurie G. W., Martin G. R. Basement membrane complexes with biological activity. Biochemistry. 1986 Jan 28;25(2):312–318. doi: 10.1021/bi00350a005. [DOI] [PubMed] [Google Scholar]
- Kubota Y., Kleinman H. K., Martin G. R., Lawley T. J. 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. doi: 10.1083/jcb.107.4.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kubota Y., Kleinman H. K., Martin G. R., Lawley T. J. 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. doi: 10.1083/jcb.107.4.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meininger C. J., Zetter B. R. Mast cells and angiogenesis. Semin Cancer Biol. 1992 Apr;3(2):73–79. [PubMed] [Google Scholar]
- Meng H., Marchese M. J., Garlick J. A., Jelaska A., Korn J. H., Gailit J., Clark R. A., Gruber B. L. 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. doi: 10.1111/1523-1747.ep12326075. [DOI] [PubMed] [Google Scholar]
- Montesano R., Orci L. Tumor-promoting phorbol esters induce angiogenesis in vitro. Cell. 1985 Sep;42(2):469–477. doi: 10.1016/0092-8674(85)90104-7. [DOI] [PubMed] [Google Scholar]
- Montesano R., Pepper M. S., Möhle-Steinlein U., Risau W., Wagner E. F., 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. doi: 10.1016/0092-8674(90)90009-4. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1111/j.1365-3083.1995.tb03628.x. [DOI] [PubMed] [Google Scholar]
- Pennington D. W., Lopez A. R., Thomas P. S., Peck C., Gold W. M. Dog mastocytoma cells produce transforming growth factor beta 1. J Clin Invest. 1992 Jul;90(1):35–41. doi: 10.1172/JCI115853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Qu Z., Liebler J. M., Powers M. R., Galey T., Ahmadi P., Huang X. N., Ansel J. C., Butterfield J. H., Planck S. R., Rosenbaum J. T. 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. [PMC free article] [PubMed] [Google Scholar]
- Rizzo V., DeFouw D. O. Mast cell activation accelerates the normal rate of angiogenesis in the chick chorioallantoic membrane. Microvasc Res. 1996 Nov;52(3):245–257. doi: 10.1006/mvre.1996.0062. [DOI] [PubMed] [Google Scholar]
- Roche W. R. 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. doi: 10.1002/ijc.2910360617. [DOI] [PubMed] [Google Scholar]
- Sakai K., Ren S., Schwartz L. B. 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. doi: 10.1172/JCI118523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwartz L. B., Lewis R. A., Austen K. F. Tryptase from human pulmonary mast cells. Purification and characterization. J Biol Chem. 1981 Nov 25;256(22):11939–11943. [PubMed] [Google Scholar]
- Schwartz L. B. Tryptase: a mast cell serine protease. Methods Enzymol. 1994;244:88–100. doi: 10.1016/0076-6879(94)44008-5. [DOI] [PubMed] [Google Scholar]
- Sommerhoff C. P., Söllner C., Mentele R., Piechottka G. P., Auerswald E. A., 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. doi: 10.1515/bchm3.1994.375.10.685. [DOI] [PubMed] [Google Scholar]
- Stack M. S., Johnson D. A. Human mast cell tryptase activates single-chain urinary-type plasminogen activator (pro-urokinase). J Biol Chem. 1994 Apr 1;269(13):9416–9419. [PubMed] [Google Scholar]
- Xia H. Z., Kepley C. L., Sakai K., Chelliah J., Irani A. M., Schwartz L. B. 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] [Google Scholar]
- Zimrin A. B., 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. doi: 10.1006/bbrc.1995.2178. [DOI] [PubMed] [Google Scholar]