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Mast-cell-mediated angiogenesis: a novel experimental model using the rat mesentery

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Virchows Archiv B

Summary

The angiogenic effect of autogenous secreting mast cells (MCs) was studied using a novel experimental approach. The virtually avascular membranous rat mesentery was used as test tissue. The activation of MCs was elicited by repeated intraperitoneal injections of the MC-secretagogue compound 48/80, which per se appears inert from the proliferogenic and angiogenic point of view. Angiogenesis was quantitated histologically and expressed the number of vessels/unit length of mesentery. The smallest vessels recognized had a luminal area of approximately 7–8 μm2 (corresponding to a circular diameter of 3.0-3.2 μm). Seven to ten days after MC-activation ended, the number of blood vessels had increased 7- to 6-fold. A retrogressive reaction occurred between days 21 and 38 after treatment, when the number of vessels had essentially normalized, as compared to vehicle-treated controls.

The present study, introducing the membranous mesentery as a model for quantitative angiogenetic studies, provides evidence that MCs can induce angiogenesis, which is new. The possible therapeutic implication of this finding is noteworthy.

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References

  • Adamson IYR, Bowden DH (1974) The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 77:185–190

    PubMed  CAS  Google Scholar 

  • Aso Y, Yoneda K, Kikkawa Y (1976) Morphologic and biochemical study of pulmonary changes induced by bleomycin in mice. Lab Invest 35:558–568

    PubMed  CAS  Google Scholar 

  • Atkins FM, Friedman MM, Metcalfe DD (1985) Biochemical and microscopic evidence for the internalization and degradation of heparin-containing mast cell granules by bovine endothelial cells. Lab Invest 52:278–286

    PubMed  CAS  Google Scholar 

  • Azizkhan RG, Azizkhan JC, Zetter BR, Folkman J (1980) Mast cell heparin stimulates migration of capillary endothelial cells in vitro. J Exp Med 152:931–944

    Article  PubMed  CAS  Google Scholar 

  • BenEzra D (1978) Neovasculogenic ability of prostaglandins, growth factors, and synthetic chemoattractants. Am J Ophthal 86:455–461

    PubMed  CAS  Google Scholar 

  • Birkedal-Hansen H, Cobb CM, Taylor RE, Fullmer HM (1976) Activation of fibroblast procollagenase by mast cell proteases. Biochim Biophys Acta 438:273–286

    PubMed  CAS  Google Scholar 

  • Bivin WS, Crawford MP, Brewer NR (1979) Morphophysiology. In: Baker HJ, Lindsey JR, Weisbroth SD (eds) The laboratory rat, vol I. Biology and diseases. Academic Press, New York, p 83

    Google Scholar 

  • Boréus LO (1960) A comparison of mast-cell reactions in the rat, hamster and guinea-pig. Acta Physiol Scand 49:251–260

    PubMed  Google Scholar 

  • Castellot Jr JJ, Karnovsky MJ, Spiegelman BM (1982) Differentiation-dependent stimulation of neovascularization and endothelial cell chemotaxis by 3T3 adipocytes. Proc Natl Acad Sci 79:5597–5601

    Article  PubMed  Google Scholar 

  • Crum R, Szabo S, Folkman J (1985) A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science 230:1375–1378

    Article  PubMed  CAS  Google Scholar 

  • Douglas WW (1985) Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In: Gillman AG, Goodman LS, Rall TW, Murad F (eds) The pharmacological basis of therapeutics. MacMillan, New York, p 613

    Google Scholar 

  • Dukor P, Kallos P, Schlumberger DH, West GB (1980) Editorial introduction in “Pseudoallergic reactions, vol 1: Genetic aspects and anaphylactoid reactions”. Karger, Basel, p IX-XIV

    Google Scholar 

  • Folkman J (1985a) Tumor angiogenesis. In: Klein G, Weinhouse S (eds) Advances in cancer research, vol 43. Academic Press, New York, pp 175–203

    Google Scholar 

  • Folkman J (1985b) Regulation of angiogenesis: a new function of heparin. Biochem Pharmacol 34:905–909

    Article  PubMed  CAS  Google Scholar 

  • Folkman J (1986) How is blood vessel growth regulated in normal and neoplastic tissue? -GHA Clowes memorial award lecture. Cancer Res 46:467–473

    PubMed  CAS  Google Scholar 

  • Folkman J, Cotran RS (1976) Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol 16:207–248

    PubMed  CAS  Google Scholar 

  • Folkman J, Taylor S, Spillberg C (1983 a) The role of heparin. In: Development of the vascular system. CIBA Foundation symposium 100. Pitman, London, pp 132–149

    Chapter  Google Scholar 

  • Folkman J, Langer R, Linhardt RJ, Haudenschild C, Taylor S (1983 b) Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 221:719–725

    Article  PubMed  CAS  Google Scholar 

  • Form DM, Auerbach R (1983) PGE2 and angiogenesis. Proc Soc Exp Biol Med 172:214–218

    PubMed  CAS  Google Scholar 

  • Franzén L (1981) Further studies on the relationship between drug-induced mast-cell secretion and local cell proliferation. Acta Pathol Microbiol Immunol Scand A 89:57–62

    Google Scholar 

  • Franzén L, Norrby K (1977) Different proliferative responsiveness of fibroblasts and mesothelial cells in the rat mesentery following administration of compound 48/80 at various hours of the day. Virchows Arch [Cell Pathol] 24:91–99

    Google Scholar 

  • Franzén L, Norrby K (1980) Local mitogenic effect of tissue mast cell secretion. Cell Tissue Kinet 13:635–642

    PubMed  Google Scholar 

  • Franzén L, Norrby K (1982) Immunological challenge causes mitogenic stimulation in normal connective tissue cells. Acta Pathol Microbiol Immunol Scand A 90:385–389

    PubMed  Google Scholar 

  • Fraser RA, Simpson JG (1983) Role of mast cells in experimental tumour angiogenesis. In: Development of the vascular system. CIBA Foundation symposium 100. Pitman, London, pp 120–131

    Chapter  Google Scholar 

  • Fraser RA, Stalker AL (1981) Endothelial cell growth stimulation in vitro. In: Gaehtgens P (ed) Recent advances in microcirculatory research. Karger, Basel (Bibl Anat 20), pp 633–636

    Google Scholar 

  • Fraser RA, Ellis EM, Stalker AL (1979) Experimental angiogenesis in the chorio-allantoic membrane. Bibl Anat 18:25–27

    PubMed  Google Scholar 

  • Glimelius B, Busch C, Höök M (1978) Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 12:773–782

    Article  PubMed  CAS  Google Scholar 

  • Goto T, Befus D, Low R, Bienenstock J (1984) Mast cell heterogeneity and hyperplasia in bleomycin-induced pulmonary fibrosis of rats. Am Rev Respir Dis 130:797–802

    PubMed  CAS  Google Scholar 

  • Gross JL, Moscatelli D, Jaffe EA, Rifkin DB (1982) Plasminogen activator and collagenase production by cultured capillary endothelial cells. J Cell Biol 95:974–981

    Article  PubMed  CAS  Google Scholar 

  • Gross JL, Moscatelli D, Rifkin DB (1983) Increased capillary endothelial cell protease activity in response to angiogenic stimuli in vitro. Proc Natl Acad Sci (USA) 80:2623–2627

    Article  CAS  Google Scholar 

  • Hay ED (1983) Introductory remarks. In: Hay ED (ed) Cell biology of extracellular matrix. Plenum Press, New York, pp 1–4

    Google Scholar 

  • Keiser HD (1980) The effect of lysosomal enzymes on extracellular substances. In: Weissman G (ed) The cell biology of inflammation. Elsevier/North Holland, Amsterdam, pp 431–467

    Google Scholar 

  • Klagsbrun M, Shing Y (1985) Heparin affinity of anionic and cationic capillary endothelial cell growth factors: analysis of hypothalamus-derived growth factors and fibroblast growth factors. Proc Natl Acad Sci (USA) 82:805–809

    Article  CAS  Google Scholar 

  • Kumar P, Kumar S (1984) Mast cells and angiogenesis. JR Soc Med 77:1063–1064

    CAS  Google Scholar 

  • Lagunoff D (1968) The properties of mast cell proteases. Biochem Pharmacol Suppl: 221–227

  • Leighton J (1967) The spread of cancer explored in the embryonated egg. In: Leighton J (ed) The spread of cancer. Academic Press, New York, pp 115–192

    Google Scholar 

  • Lobb RR, Alderman EM, Fett JW (1985) Induction of angiogenesis by bovine brain derived class 1 heparin-binding growth factor. Biochemistry 24:4969–4973

    Article  PubMed  CAS  Google Scholar 

  • Lopez R, Rand LI, Zetter BR (1982) Absence of mast cells in diabetic retinopathy. Microvasc Res 24:87–93

    Article  PubMed  CAS  Google Scholar 

  • Metcalfe DD, Kaliner M (1981) Mast cells and basophils. In: Oppenheim JJ, Rosenstreich DL, Potter M (eds) Cellular functions in immunity and inflammation. Edward Arnold, London, pp 301–322

    Google Scholar 

  • Mota I, Vugman J (1956) Action of compound 48/80 on the mast cells and histamine content of guinea-pig tissues. Br J Pharmacol 11:304–307

    CAS  Google Scholar 

  • Norrby K (1973) Effect of heparin, histamine and serotonin on the density-dependent inhibition of replication in two fibroblastic cell lines. Virchows Arch [Cell Pathol] 15:75–93

    CAS  Google Scholar 

  • Norrby K (1980) Mast cell histamine, a local mitogen acting via H2-receptors in nearby tissue cells. Virchows Arch [Cell Pathol] 34:13–20

    Article  CAS  Google Scholar 

  • Norrby K (1981) On the 48/80-induced secretion of tissue mast cells and its mitogenic effect on nearby cells in the intact rat. Virchows Arch [Cell Pathol] 38:57–65

    Article  CAS  Google Scholar 

  • Norrby K (1985) Evidence of mast-cell histamine being mitogenic in intact tissue. Agents Actions 16:287–290

    Article  PubMed  CAS  Google Scholar 

  • Norrby K, Eneström S (1984) Cellular and extracellular changes following mast-cell secretion in avascular rat mesentery. An electron-microscopic study. Cell Tiss Res 235:339–345

    Article  CAS  Google Scholar 

  • Norrby K, Enerbäck L, Franzén L (1976) Mast cell activation and tissue cell proliferation. Cell Tiss Res 170:289–303

    Article  CAS  Google Scholar 

  • Norrby K, Bergström S, Druvefors P (1983) Hyperplasia and growth of the true mesentery in the diabetic rat. Acta Pathol Microbiol Immunol Scand A 91:195–202

    PubMed  CAS  Google Scholar 

  • Paton WDM (1957) Histamine release by compounds of simple chemical structure. Pharmacol Rev 9:269–327

    PubMed  CAS  Google Scholar 

  • Riley JF, West GB (1955) Histamine liberation in the rat and mouse. Arch Pharmacodyn 102:304–313

    CAS  Google Scholar 

  • Roche WR (1985 a) Mast cells and tumors. The specific enhancement of tumor proliferation in vitro. Am J Pathol 119:57–64

    PubMed  CAS  Google Scholar 

  • Roche WR (1985 b) Mast cells and tumour angiogenesis: the tumour-mediated release of an endothelial growth factor from mast cells. Int J Cancer 36:721–728

    Article  PubMed  CAS  Google Scholar 

  • Rothschild AM (1970) Mechanisms of histamine release by compound 48/80. Br J Pharmacol 38:253–262

    PubMed  CAS  Google Scholar 

  • Schor AM, Schor SL (1983) Tumour angiogenesis. J Pathol 141:385–413

    Article  PubMed  CAS  Google Scholar 

  • Schwartz LB, Austen KF (1982) Mast cells and mediators. In: Lachmann PJ, Peters DK (eds) Clinical aspects of immunology (4th edition) vol 1. Blackwell, Oxford, pp 130–157

    Google Scholar 

  • Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M (1984) Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 223:1296–1298

    Article  PubMed  CAS  Google Scholar 

  • Sholley MM, Ferguson GP, Seibel HR, Montour JL, Wilson JD (1984) Mechanisms on neovascularization. Vascular sprouting can occur without proliferation of endothelial cells. Lab Invest 51:624–634

    PubMed  CAS  Google Scholar 

  • Starcher BC, Kuhn C, Overton JE (1978) Increased elastin and collagen content in the lungs of hamsters receiving an intraperitoneal injection of bleomycin. Am Rev Resp Dis 117:299–305

    PubMed  CAS  Google Scholar 

  • Subba Rao PV, Friedman MM, Atkins FM, Metcalfe DD (1983) Phagocytosis of mast cell granules by cultured fibroblasts. J Immunol 130:341–349

    Google Scholar 

  • Taylor S, Folkman J (1982) Protamine is an inhibitor of angiogenesis. Nature 297:307–312

    Article  PubMed  CAS  Google Scholar 

  • Terranova VP, DiFlorio R, Lyall RM, Hic S, Friesel R, Maciag T (1985) Human endothelial cells are chemotactic to endothelial cell growth factor and heparin. J Cell Biol 101:2330–2334

    Article  PubMed  CAS  Google Scholar 

  • Thornton SC, Mueller SN, Levine EM (1983) Human endothelial cells: use of heparin in cloning and long-term serial cultivation. Science 22:623–62

    Article  Google Scholar 

  • Thrall RS, McCormick JR, Jack RM, McReynolds RA, Ward PA (1979) Bleomycin-induced pulmonary fibrosis in the rat. Am J Pathol 95:117–130

    PubMed  CAS  Google Scholar 

  • Ungari S, Katari RS, Alessandri G, Gullino PM (1985) Cooperation between fibronectin and heparin in the mobilization of capillary endothelium. Invasion Metastasis 5:193–205

    PubMed  CAS  Google Scholar 

  • Weiss JB, Hill CR, McLaughlin B, Elstow S (1983) Potentiating effect of heparin in the activation of procollagenase by a low-Mr angiogenesis factor. FEBS 163:62–65

    Article  CAS  Google Scholar 

  • Zauberman H, Michaelson IC, Bergmann F, Maurice DM (1969) Stimulation of neovascularization of the cornea by biogenic amines. Exptl Eye Res 8:77–8

    Article  CAS  Google Scholar 

  • Zetter BR (1980) Migration of capillary endothelial cells is stimulated by tumour-derived growth factors. Nature 285:41–43

    Article  PubMed  CAS  Google Scholar 

  • Ziche M, Jones J, Gullino PM (1982) Role of prostaglandin El and copper in angiogenesis. J Natl Cancer Inst 69:475–482

    PubMed  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Pathology, University of Göteborg, Sahlgren’s Hospital, S-413 45, Göteborg, Sweden

    Klas Norrby, Anders Jakobsson & Jan Sörbo

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  1. Klas Norrby
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  2. Anders Jakobsson
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  3. Jan Sörbo
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Supported by grants from the Swedish Medical Research Council, Project 5942

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Norrby, K., Jakobsson, A. & Sörbo, J. Mast-cell-mediated angiogenesis: a novel experimental model using the rat mesentery. Virchows Archiv B Cell Pathol 52, 195–206 (1986). https://doi.org/10.1007/BF02889963

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