Advertisement

Multiple Roles of Proteases in Angiogenesis

  • Ester M. Weijers
  • Victor W. M. van HinsberghEmail author
Chapter

Abstract

Proteases play an important role in various aspects of angiogenesis. First, pericellular proteolysis facilitates matrix degradation as well as migration and invasion of capillary sprouts into its surrounding matrix. (Membrane-type) matrix metalloproteases [(MT-)MMPs], ADAM(TS) metalloproteases, serine proteases, their inhibitors, and occasionally cysteine proteases are important players in pericellular proteolysis. The specific location and short exposure of protease activity can be explained by a tread-milling model with internalization of protease–receptor complexes as was proposed for MT1-MMP/MMP2 and urokinase/urokinase receptor complexes. Second, proteolytic events play a role in regulating VEGF-induced sprouting, such as proteasomal degradation of hypoxia inducible factors (HIFs), Notch-mediated cell signaling, and turnover of VEGF receptors. Third, proteases can activate and modify growth factors and receptors and thus generate split products with new biological functions and contribute to cell recruitment. Proteases likely also contribute to formation of anastomoses, which is required to restore circulation. Finally, new biological functions are also acquired by generation of split products from and modifications of matrix proteins. They include angiogenesis-inhibiting matrikines, and modified fibrin forms with altered angiogenic properties, which may bear perspective for tissue engineering applications.

Keywords

Matrix metalloproteinases Cysteine proteases VEGF Hypoxia HIF Notch signaling 

Notes

Acknowledgments

This work was supported by grants of The Netherlands Institute for Regenerative Medicine (NIRM, workpackage hypoxia and angiogenesis).

References

  1. 1.
    Carmeliet P, Collen D (1998) Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res 91(6):255–285PubMedCrossRefGoogle Scholar
  2. 2.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174PubMedCrossRefGoogle Scholar
  3. 3.
    van Hinsbergh VWM, Engelse MA, Quax PH (2006) Pericellular proteases in angiogenesis and vasculogenesis. Arterioscler Thromb Vasc Biol 26(4):716–728PubMedCrossRefGoogle Scholar
  4. 4.
    Verloop RE, Koolwijk P, van Zonneveld AJ, van Hinsbergh VW (2009) Proteases and receptors in the recruitment of endothelial progenitor cells in neovascularization. Eur Cytokine Netw 20(4):207–219PubMedGoogle Scholar
  5. 5.
    van Hinsbergh VWM, Koolwijk P (2008) Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 78(2):203–212PubMedCrossRefGoogle Scholar
  6. 6.
    Davis GE, Stratman AN, Sacharidou A, Koh W (2011) Molecular basis for endothelial lumen formation and tubulogenesis during vasculogenesis and angiogenic sprouting. Int Rev Cell Mol Biol 288:101–165PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Lopez-Otin C, Bond JS (2008) Proteases: multifunctional enzymes in life and disease. J Biol Chem 283(45):30433–30437PubMedCrossRefGoogle Scholar
  8. 8.
    Blasi F, Carmeliet P (2002) uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 3(12):932–943PubMedCrossRefGoogle Scholar
  9. 9.
    Andreasen PA, Egelund R, Petersen HH (2000) The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 57(1):25–40PubMedCrossRefGoogle Scholar
  10. 10.
    Roy R, Zhang B, Moses MA (2006) Making the cut: protease-mediated regulation of angiogenesis. Exp Cell Res 312(5):608–622PubMedCrossRefGoogle Scholar
  11. 11.
    Lijnen HR (2001) Plasmin and matrix metalloproteinases in vascular remodeling. Thromb Haemost 86(1):324–333PubMedGoogle Scholar
  12. 12.
    Van De Craen B, Scroyen I, Vranckx C, Compernolle G, Lijnen HR, Declerck PJ et al (2012) Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1. Thromb Res 129(4):e126–e133CrossRefGoogle Scholar
  13. 13.
    Syrovets T, Simmet T (2004) Novel aspects and new roles for the serine protease plasmin. Cell Mol Life Sci 61(7–8):873–885PubMedCrossRefGoogle Scholar
  14. 14.
    Matsuno H (2006) Alpha2-antiplasmin on cardiovascular diseases. Curr Pharm Des 12(7):841–847PubMedCrossRefGoogle Scholar
  15. 15.
    Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Newby AC (2005) Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 85(1):1–31PubMedCrossRefGoogle Scholar
  17. 17.
    Spinale FG, Janicki JS, Zile MR (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112(1):195–208PubMedCrossRefGoogle Scholar
  18. 18.
    Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92(8):827–839PubMedCrossRefGoogle Scholar
  19. 19.
    Nagase H, Woessner JFJ (1999) Matrix metalloproteinases. J Biol Chem 274(31):21491–21494PubMedCrossRefGoogle Scholar
  20. 20.
    Butler GS, Overall CM (2009) Updated biological roles for matrix metalloproteinases and new “intracellular” substrates revealed by degradomics. Biochemistry 48(46):10830–10845PubMedCrossRefGoogle Scholar
  21. 21.
    Rodriguez D, Morrison CJ, Overall CM (2010) Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta 1803(1):39–54PubMedCrossRefGoogle Scholar
  22. 22.
    Handsley MM, Edwards DR (2005) Metalloproteinases and their inhibitors in tumor angiogenesis. Int J Cancer 115(6):849–860PubMedCrossRefGoogle Scholar
  23. 23.
    Bauvois B (2012) New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta 1825(1):29–36PubMedGoogle Scholar
  24. 24.
    Williams KC, Coppolino MG (2011) Phosphorylation of membrane type 1-matrix metalloproteinase (MT1-MMP) and its vesicle-associated membrane protein 7 (VAMP7)-dependent trafficking facilitate cell invasion and migration. J Biol Chem 286(50):43405–43416PubMedCrossRefGoogle Scholar
  25. 25.
    Galvez BG, Matias-Roman S, Yanez-Mo M, Vicente-Manzanares M, Sanchez-Madrid F, Arroyo AG (2004) Caveolae are a novel pathway for membrane-type 1 matrix metalloproteinase traffic in human endothelial cells. Mol Biol Cell 15(2):678–687PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803(1):55–71PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Vagima Y, Avigdor A, Goichberg P, Shivtiel S, Tesio M, Kalinkovich A et al (2009) MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization. J Clin Invest 119(3):492–503PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Mascall KS, Small GR, Gibson G, Nixon GF (2012) Sphingosine-1-phosphate-induced release of TIMP-2 from vascular smooth muscle cells inhibits angiogenesis. J Cell Sci 125(Pt 9):2267–2275PubMedCrossRefGoogle Scholar
  29. 29.
    Seo DW, Li H, Guedez L, Wingfield PT, Diaz T, Salloum R et al (2003) TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114(2):171–180PubMedCrossRefGoogle Scholar
  30. 30.
    Kumar S, Rao N, Ruowen G (2012) Emerging roles of ADAMTSs in angiogenesis and cancer. Cancers 4(4):1252–1299PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Kostoulas G, Lang A, Nagase H, Baici A (1999) Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases. FEBS Lett 455(3):286–290PubMedCrossRefGoogle Scholar
  32. 32.
    Urbich C, Heeschen C, Aicher A, Sasaki K, Bruhl T, Farhadi MR et al (2005) Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat Med 11(2):206–213PubMedCrossRefGoogle Scholar
  33. 33.
    Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6(10):764–775PubMedCrossRefGoogle Scholar
  34. 34.
    Kobayashi H, Moniwa N, Sugimura M, Shinohara H, Ohi H, Terao T (1993) Effects of membrane-associated cathepsin B on the activation of receptor-bound prourokinase and subsequent invasion of reconstituted basement membranes. Biochim Biophys Acta 1178(1):55–62PubMedCrossRefGoogle Scholar
  35. 35.
    Sakamoto T, Seiki M (2010) A membrane protease regulates energy production in macrophages by activating hypoxia-inducible factor-1 via a non-proteolytic mechanism. J Biol Chem 285(39):29951–29964PubMedCrossRefGoogle Scholar
  36. 36.
    Nishida C, Kusubata K, Tashiro Y, Gritli I, Sato A, Ohki-Koizumi M et al (2012) MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemokine/cytokine gene transcription within niche cells. Blood 119(23):5405–5416PubMedCrossRefGoogle Scholar
  37. 37.
    Chen TT, Luque A, Lee S, Anderson SM, Segura T, Iruela-Arispe ML (2010) Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J Cell Biol 188(4):595–609PubMedCrossRefGoogle Scholar
  38. 38.
    Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169(4):681–691PubMedCrossRefGoogle Scholar
  39. 39.
    Nakayama M, Nakayama A, van Lessen M, Yamamoto H, Hoffmann S, Drexler HCA et al (2013) Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat Cell Biol 15(3):249–260PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM et al (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12(10):943–953PubMedCrossRefGoogle Scholar
  41. 41.
    Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887PubMedCrossRefGoogle Scholar
  42. 42.
    Funahashi Y, Shawber CJ, Sharma A, Kanamaru E, Choi YK, Kitajewski J (2011) Notch modulates VEGF action in endothelial cells by inducing matrix metalloprotease activity. Vasc Cell 3(1):2PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Kamei M, Saunders WB, Bayless KJ, Dye L, Davis GE, Weinstein BM (2006) Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442(7101):453–456PubMedCrossRefGoogle Scholar
  44. 44.
    Strilic B, Kucera T, Eglinger J, Hughes MR, McNagny KM, Tsukita S et al (2009) The molecular basis of vascular lumen formation in the developing mouse aorta. Dev Cell 17(4):505–515PubMedCrossRefGoogle Scholar
  45. 45.
    Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H et al (2002) CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J 21(15):3949–3959PubMedCrossRefGoogle Scholar
  46. 46.
    Tjwa M, Sidenius N, Moura R, Jansen S, Theunissen K, Andolfo A et al (2009) Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells. J Clin Invest 119(4):1008–1018PubMedCentralPubMedGoogle Scholar
  47. 47.
    Uekita T, Itoh Y, Yana I, Ohno H, Seiki M (2001) Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J Cell Biol 155(7):1345–1356PubMedCrossRefGoogle Scholar
  48. 48.
    Gonzalo P, Guadamillas MC, Hernandez-Riquer MV, Pollan A, Grande-Garcia A, Bartolome RA et al (2010) MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling. Dev Cell 18(1):77–89PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Sacharidou A, Koh W, Stratman AN, Mayo AM, Fisher KE, Davis GE (2010) Endothelial lumen signaling complexes control 3D matrix-specific tubulogenesis through interdependent Cdc42- and MT1-MMP-mediated events. Blood 115(25):5259–5269PubMedCrossRefGoogle Scholar
  50. 50.
    Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840PubMedCrossRefGoogle Scholar
  51. 51.
    Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y (2002) Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem 277(39):36288–36295PubMedCrossRefGoogle Scholar
  52. 52.
    McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I et al (2001) Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276(47):43503–43508PubMedCrossRefGoogle Scholar
  53. 53.
    Mourad JJ, Des Guetz G, Debbabi H, Levy BI (2008) Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol 19(5):927–934PubMedCrossRefGoogle Scholar
  54. 54.
    van der Veldt AAM, de Boer MP, Boven E, Eringa EC, van den Eertwegh AJM, van Hinsbergh VW et al (2010) Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib. Anticancer Drugs 21(4):439–446PubMedCrossRefGoogle Scholar
  55. 55.
    Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P et al (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6(3):315–325PubMedCrossRefGoogle Scholar
  56. 56.
    Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, Thorpe PE et al (2002) Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21(46):7011–7026PubMedCrossRefGoogle Scholar
  57. 57.
    Arroyo AG, Iruela-Arispe ML (2010) Extracellular matrix, inflammation, and the angiogenic response. Cardiovasc Res 86(2):226–235PubMedCrossRefGoogle Scholar
  58. 58.
    Barczyk M, Carracedo S, Gullberg D (2010) Integrins. Cell Tissue Res 339(1):269–280PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Laurens N, Koolwijk P, de Maat MP (2006) Fibrin structure and wound healing. J Thromb Haemost 4(5):932–939PubMedCrossRefGoogle Scholar
  60. 60.
    Holm B, Nilsen DW, Kierulf P, Godal HC (1985) Purification and characterization of 3 fibrinogens with different molecular weights obtained from normal human plasma. Thromb Res 37(1):165–176PubMedCrossRefGoogle Scholar
  61. 61.
    Henschen-Edman AH (2001) Fibrinogen non-inherited heterogeneity and its relationship to function in health and disease. Ann N Y Acad Sci 936:580–593PubMedCrossRefGoogle Scholar
  62. 62.
    de Maat MP, Verschuur M (2005) Fibrinogen heterogeneity: inherited and noninherited. Curr Opin Hematol 12(5):377–383PubMedCrossRefGoogle Scholar
  63. 63.
    Nakashima A, Sasaki S, Miyazaki K, Miyata T, Iwanaga S (1992) Human fibrinogen heterogeneity: the COOH-terminal residues of defective A alpha chains of fibrinogen II. Blood Coagul Fibrinolysis 3(4):361–370PubMedCrossRefGoogle Scholar
  64. 64.
    Manten GTR, Sikkema JM, Franx A, Hameeteman TM, Visser GHA, de Groot PG et al (2003) Increased high molecular weight fibrinogen in pre-eclampsia. Thromb Res 111(3):143–147PubMedCrossRefGoogle Scholar
  65. 65.
    Danesh J, Lewington S, Thompson SG, Lowe GDO, Collins R, Kostis JB et al (2005) Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 294(14):1799–1809PubMedGoogle Scholar
  66. 66.
    Holm B, Godal HC (1984) Quantitation of the three normally-occurring plasma fibrinogens in health and during so-called “acute phase” by SDS electrophoresis of fibrin obtained from EDTA-plasma. Thromb Res 35(3):279–290PubMedCrossRefGoogle Scholar
  67. 67.
    Kaijzel EL, Koolwijk P, van Erck MG, van Hinsbergh VWM, de Maat MP (2006) Molecular weight fibrinogen variants determine angiogenesis rate in a fibrin matrix in vitro and in vivo. J Thromb Haemost 4(9):1975–1981PubMedCrossRefGoogle Scholar
  68. 68.
    Weijers EM, Van Wijhe MH, Joosten L, Horrevoets AJ, de Maat MP, van Hinsbergh VWM et al (2010) Molecular weight fibrinogen variants alter gene expression and functional characteristics of human endothelial cells. J Thromb Haemost 8(12):2800–2809PubMedCrossRefGoogle Scholar
  69. 69.
    Zucker S, Cao J (2009) Selective matrix metalloproteinase (MMP) inhibitors in cancer therapy: ready for prime time? Cancer Biol Ther 8(24):2371–2373PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392PubMedCrossRefGoogle Scholar
  71. 71.
    Ulisse S, Baldini E, Sorrenti S, D’Armiento M (2009) The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr Cancer Drug Targets 9(1):32–71PubMedCrossRefGoogle Scholar
  72. 72.
    Overall CM, Blobel CP (2007) In search of partners: linking extracellular proteases to substrates. Nat Rev Mol Cell Biol 8(3):245–257PubMedCrossRefGoogle Scholar
  73. 73.
    Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR et al (2002) Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109(5):625–637PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Segers VFM, Tokunou T, Higgins LJ, MacGillivray C, Gannon J, Lee RT (2007) Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation 116(15):1683–1692PubMedCrossRefGoogle Scholar
  75. 75.
    Dai J, Agelan A, Yang A, Zuluaga V, Sexton D, Colman RW et al (2012) Role of plasma kallikrein-kinin system activation in synovial recruitment of endothelial progenitor cells in experimental arthritis. Arthritis Rheum 64(11):3574–3582PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Reing JE, Zhang L, Myers-Irvin J, Cordero KE, Freytes DO, Heber-Katz E et al (2009) Degradation products of extracellular matrix affect cell migration and proliferation. Tissue Eng Part A 15(3):605–614PubMedCrossRefGoogle Scholar
  77. 77.
    Iwakura A, Shastry S, Luedemann C, Hamada H, Kawamoto A, Kishore R et al (2006) Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix metalloproteinase-9. Circulation 113(12):1605–1614PubMedCrossRefGoogle Scholar
  78. 78.
    Deryugina EI, Quigley JP (2010) Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta 1803(1):103–120PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Xiao Q, Zhang F, Lin L, Fang C, Wen G, Tsai TN et al (2013) Functional role of matrix metalloproteinase-8 in stem/progenitor cell migration and their recruitment into atherosclerotic lesions. Circ Res 112(1):35–47PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Ester M. Weijers
    • 1
  • Victor W. M. van Hinsbergh
    • 1
    Email author
  1. 1.Laboratory for Physiology, Institute for Cardiovascular ResearchVU University Medical CenterAmsterdamThe Netherlands

Personalised recommendations