Advertisement

Serpins in Angiogenesis

  • Czeslaw S. Cierniewski
  • Joanna BoncelaEmail author
Chapter

Abstract

Serpins (serine proteinase inhibitors) are the largest superfamily of protease inhibitors. The serpins are structurally similar but functionally diverse proteins that fold into a conserved structure and employ a unique suicide substrate-like inhibitory mechanism. Most of them act as classical protease inhibitors, but there are also serpins that inhibit other types of proteinases, e.g., caspases, or have different, noninhibitory functions, e.g., hormone transport. Serpins are involved in regulation of numerous biological pathways that initiate inflammation, coagulation, fibrinolysis, complement activation responses, apoptosis, extracellular matrix composition, and angiogenesis. The following serpins have been identified as potential regulators of angiogenesis: plasminogen activator inhibitor type 1 (PAI-1), kallistatin, protein C inhibitor, angiotensinogen, maspin, antithrombin, nexin-1, and pigment epithelial-derived factor. They exert mainly antiangiogenic activity, by inhibition of proteolytic processes in which serine proteases and matrix metalloproteinases (MMPs) are key players. Among them, PAI-1 appears to be the most controversial serpin in angiogenesis; it may act both as a pro- and antiangiogenic factor, depending upon the type of cells and existing conditions. Taken together, serpins remarkably contribute to vessels formation process; they are able to affect more than one of the angiogenic steps and their activity extend beyond the inhibition of target proteinases.

Keywords

Serine protease inhibitors Plasminogen activator inhibitor type 1 Extracellular matrix Endothelial cells migration Plasmin-dependent proteolysis 

Notes

Acknowledgment

This work was supported by Projects DEC-2011/01/B/NZ3/00194 (J.B.) and DEC-2011/02/A/NZ3/00068 (C.S.C.).

References

  1. 1.
    Irving JA, Pike RN, Lusk AM, Whisstock JC (2000) Phylogeny of the serpent super family: implications of patterns of amino acid conservation for structure and function. Genome Res 10:1845–1864PubMedGoogle Scholar
  2. 2.
    Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC (2006) An overview of the serpin superfamily. Genome Biol 7:216–226PubMedCentralPubMedGoogle Scholar
  3. 3.
    Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O’Donnell E, Salvesen GS, Travis J, Whisstock JC (2001) The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 276:33293–33296PubMedGoogle Scholar
  4. 4.
    Potempa J, Korzus E, Travis J (1994) The serpin superfamily of proteinase inhibitors: structure, function, and regulation. J Biol Chem 269:15957–15960PubMedGoogle Scholar
  5. 5.
    Irving JA, Pike RN, Dai W, Bromme D, Worrall DM, Silverman GA, Coetzer TH, Dennison C, Bottomley SP, Whisstock JC (2002) Evidence that serpin architecture intrinsically supports papain-like cysteine protease inhibition: engineering alpha(1)-antitrypsin to inhibit cathepsin proteases. Biochemistry 41:4998–5004PubMedGoogle Scholar
  6. 6.
    Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW (1988) Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336:257–258PubMedGoogle Scholar
  7. 7.
    Nagata K (1996) Hsp47: a collagen-specific molecular chaperone. Trends Biochem Sci 21:22–26PubMedGoogle Scholar
  8. 8.
    Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R (1994) Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263:526–529PubMedGoogle Scholar
  9. 9.
    Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu HJ, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248PubMedGoogle Scholar
  10. 10.
    Corvol P, Lamande N, Cruz A, Celerier J, Gasc JM (2003) Inhibition of angiogenesis: a new function for angiotensinogen and des(angiotensin I)angiotensinogen. Curr Hypertens Rep 5:149–154PubMedGoogle Scholar
  11. 11.
    Gettins PGW (2002) Serpin structure, mechanism and function. Chem Rev 102:4751–4803PubMedGoogle Scholar
  12. 12.
    Zhou A, Carrell RW, Huntington JA (2001) The serpin inhibitory mechanism is critically dependent on the length of the reactive center loop. J Biol Chem 276:27541–27547PubMedGoogle Scholar
  13. 13.
    Huntington JA, Read RJ, Carrell RW (2000) Structure of a serpin-protease complex shows inhibition by deformation. Nature 407:923–926PubMedGoogle Scholar
  14. 14.
    Lomas DA, Mahadeva R (2002) Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 110:1585–1590PubMedCentralPubMedGoogle Scholar
  15. 15.
    Chow MK, Lomas DA, Bottomley SP (2004) Promiscuous beta-strand interactions and the conformational diseases. Curr Med Chem 11:491–499PubMedGoogle Scholar
  16. 16.
    Mast AE, Enghild JJ, Salvesen G (1991) Conformation of the reactive site loop of alpha 1-proteinase inhibitor probed by limited proteolysis. Biochemistry 31:2720–2728Google Scholar
  17. 17.
    Whisstock J, Bottomley S (2006) Molecular gymnastics: serpin structure, folding and misfolding. Curr Opin Struct Biol 16:761–768PubMedGoogle Scholar
  18. 18.
    Hopkins PC, Carrell RW, Stone SR (1993) Effects of mutations in the hinge region of serpins. Biochemistry 32:7650–7657PubMedGoogle Scholar
  19. 19.
    Naski MC, Lawrence DA, Mosher DF, Podor TJ, Ginsburg D (1993) Kinetics of inactivation of α-thrombin by plasminogen activator inhibitor-1. Comparison of the effects of native and urea-treated forms of vitronectin. J Biol Chem 268:12367–12372PubMedGoogle Scholar
  20. 20.
    Patston PA, Church FC, Olson ST (2004) Serpin-ligand interactions. Methods 32:93–109PubMedGoogle Scholar
  21. 21.
    Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW (1997) The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci U S A 94:14693–14698Google Scholar
  22. 22.
    Olson ST, Bjork I (1991) Predominant contribution of surface approximation to the mechanism of heparin acceleration of the antithrombin-thrombin reaction. Elucidation from salt concentration effects. J Biol Chem 266:6353–6354PubMedGoogle Scholar
  23. 23.
    Nar H, Bauer M, Stassen JM, Lang D, Gils A, Declerck PJ (2000) Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivation. J Mol Biol 297:683–695PubMedGoogle Scholar
  24. 24.
    Hekman CM, Loskutoff DJ (1985) Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J Biol Chem 260:11581–11587PubMedGoogle Scholar
  25. 25.
    Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D (1990) Studies of recombinant plasminogen activator inhibitor- 1 in rabbits. Pharmacokinetics and evidence for reactivation of latent plasminogen activator inhibitor-1 in vivo. Circ Res 67:1281–1286PubMedGoogle Scholar
  26. 26.
    Declerck PJ, De Mol M, Alessi MC, Baudner S, Paques E-P, Preissner KT, Muller-Berghaus G, Collen D (1988) Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. J Biol Chem 263:15454–15461PubMedGoogle Scholar
  27. 27.
    Preissner KT, Holzhtiter S, Justus C, Muller-Berghaus G (1989) Identification and partial characterization of platelet vitronectin: evidence for complex formation with platelet-derived plasminogen activator inhibitor-1. Blood 74:1989–1996PubMedGoogle Scholar
  28. 28.
    Seiffert D, Loskutoff DJ (1999) Kinetic analysis of the interaction between type 1 plasminogen activator inhibitor and vitronectin and evidence that the bovine inhibitor binds to a thrombin-derived amino-terminal fragment of bovine vitronectin. Biochim Biophys Acta 1078:23–30Google Scholar
  29. 29.
    Lawrence DA, Berkenpas MB, Palaniappan S, Ginsburg D (1994) Localization of vitronectin binding domain in plasminogen activator inhibitor-I. J Biol Chem 269:15223–15228PubMedGoogle Scholar
  30. 30.
    Lawrence DA, Palaniappani S, Stefansson S, Olson ST, Francis-Chmura AM, Shore JD, Ginsburg D (1997) Characterization of the binding of different conformational forms of plasminogen activator inhibitor-1 to vitronectin. J Biol Chem 272:7676–7680PubMedGoogle Scholar
  31. 31.
    Thompson LC, Goswami S, Peterson CB (2011) Metals affect the structure and activity of human plasminogen activator inhibitor-1. II. Modulation of stability and protease inhibition. Protein Sci 20:366–378PubMedGoogle Scholar
  32. 32.
    Mottonen J, Strand A, Symersky J, Sweet RM, Danley DE, Geogheggan KF, Gerard RD, Goldsmith EJ (1992) Structural basis of latency in plasminogen activator inhibitor-1. Nature 355:270–273PubMedGoogle Scholar
  33. 33.
    van Meijer M, Gebbink RK, Preissner KT, Pannekoek H (1994) Determination of the vitronectin binding site on plasminogen activator inhibitor 1 (PAI-1). FEBS Lett 352:342–346PubMedGoogle Scholar
  34. 34.
    Boncela J, Papiewska I, Fijalkowska I, Walkowiak B, Cierniewski CS (2001) Acute phase protein α1-acid glycoprotein interacts with plasminogen activator inhibitor type 1 and stabilizes its inhibitory activity. J Biol Chem 276:35305–35311PubMedGoogle Scholar
  35. 35.
    Smolarczyk K, Gils A, Boncela J, Declerck PJ, Cierniewski CS (2005) Function-stabilizing mechanism of plasminogen activator inhibitor type 1 induced upon binding to alpha1-acid glycoprotein. Biochemistry 44:12384–12390PubMedGoogle Scholar
  36. 36.
    Chen SC, Henry DO, Reczek PR, Wong MK (2008) Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther 7:1227–1236PubMedGoogle Scholar
  37. 37.
    Isogai C, Laug WE, Shimada H, Declerck PJ, Stins MF, Durden DL, Erdreich-Epstein A, DeClerck YA (2001) Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res 61:5587–5594PubMedGoogle Scholar
  38. 38.
    Ploplis VA, Balsara R, Sandoval-Cooper MJ, Yin ZJ, Batten J, Modi N, Gadoua D, Donahue D, Martin JA, Castellino FJ (2004) Enhanced in vitro proliferation of aortic endothelial cells from plasminogen activator inhibitor-1-deficient mice. J Biol Chem 279:6143–6151PubMedGoogle Scholar
  39. 39.
    Soeda S, Oda M, Ochiai T, Shimeno H (2001) Deficient release of plasminogen activator inhibitor-1 from astrocytes triggers apoptosis in neuronal cells. Mol Brain Res 91:96–103PubMedGoogle Scholar
  40. 40.
    Degryse B, Neels JG, Czekay RP, Aertgeerts K, Kamikubo Y, Loskutoff DJ (2004) The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 279:22595–22604PubMedGoogle Scholar
  41. 41.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedGoogle Scholar
  42. 42.
    Carmeliet P, Collen D (2000) Transgenic mouse models in angiogenesis and cardiovascular disease. J Pathol 190:387–405PubMedGoogle Scholar
  43. 43.
    Uchiyama T, Kurabayashi M, Ohyama Y, Utsugi T, Akuzawa N, Sato M et al (2000) Hypoxia induces transcription of the plasminogen activator inhibitor-1 gene through genistein-sensitive tyrosine kinase pathways in vascular endothelial cells. Arterioscler Thromb Vasc Biol 20:1155–1161PubMedGoogle Scholar
  44. 44.
    Ulisse S, Baldini E, Sorrenti S, D’Armiento M (2009) The urokinase plasminogen activator system: a target for anticancer therapy. Curr Cancer Drug Targets 9:32–71PubMedGoogle Scholar
  45. 45.
    Bacharach E, Itin A, Keshet E (1998) Apposition-dependent induction of plasminogen activator inhibitor type 1 expression: a mechanism for balancing pericellular proteolysis during angiogenesis. Blood 92:939–945PubMedGoogle Scholar
  46. 46.
    Pepper MS (2001) Role of matrix metalloproteinases and plasminogen activator-plasmin system in angiogenesis. Arterioscler Thromb Vasc Biol 21:1104–1107PubMedGoogle Scholar
  47. 47.
    Simpson AJ, Booth NA, Moore NR, Bennett B (1991) Distribution of plasminogen activator inhibitor (PAI-1) in tissues. J Clin Pathol 44:139–143PubMedGoogle Scholar
  48. 48.
    Pepper MS, Sappino AP, Stocklin R, Montesano R, Orci L, Vassalli JD (1993) Upregulation of urokinase receptor expression on migrating endothelial cells. J Cell Biol 122:673–684PubMedGoogle Scholar
  49. 49.
    Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM (1998) Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4:923–928PubMedGoogle Scholar
  50. 50.
    Bajou K, Masson V, Gerard RD, Schmitt PM, Albert V, Praus M, Lund LR, Frandsen TL, Brunner N, Dano K, Fusenig NE, Weidle U, Carmeliet G, Loskutoff D, Collen D, Carmeliet P, Foidart JM, Noel A (2001) The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 152:777–784PubMedGoogle Scholar
  51. 51.
    Devy L, Blacher S, Grignet-Debrus C, Bajou K, Masson V, Gerard RD, Gils A, Carmeliet G, Carmeliet P, Declerck PJ, Noel A, Foidart JM (2002) The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 16:147–154PubMedGoogle Scholar
  52. 52.
    Masson V, Devy L, Grignet-Debrus C, Bernt S, Bajou K, Blacher S, Roland G, Chang Y, Fong T, Carmeliet P, Foidart JM, Noel A (2002) Mouse aortic ring assay: a new approach of the molecular genetics of angiogenesis. Biol Proced Online 4:24–31PubMedCentralGoogle Scholar
  53. 53.
    Lambert V, Munaut C, Noel A, Frankenne F, Bajou K, Gerard R, Carmeliet P, Defresne MP, Foidart JM, Rakic JM (2001) Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J 15:1021–1027PubMedGoogle Scholar
  54. 54.
    Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ (1996) Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol 134:1563–1571PubMedGoogle Scholar
  55. 55.
    Andreasen PA, Kjoller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22PubMedGoogle Scholar
  56. 56.
    Bajou K, Maillard C, Jost M, Lijnen HR, Gils A, Declerck P, Carmeliet P, Foidart JM, Noel A (2004) Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene 23:6986–6990PubMedGoogle Scholar
  57. 57.
    Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ (2000) Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasmingen activator inhibitor-1. Cancer Res 60:5839–5847PubMedGoogle Scholar
  58. 58.
    Harbeck N, Alt U, Berger U, Kates R, Kruger A, Thomssen C, Janicke F, Graeff H, Schmitt M (2000) Long term follow-up confirms prognostic impact of PAI-1 and cathepsin D and L in primary breast cancer. Int J Biol Markers 15:79–83PubMedGoogle Scholar
  59. 59.
    Tsuchiya H, Sunayama C, Okada G, Matsuda E, Tomita K, Binder BR (1997) Plasminogen activator inhibitor-1 accelerates lung metastasis formation of human fibrosarcoma cells. Anticancer Res 17:313–316PubMedGoogle Scholar
  60. 60.
    Stefansson S, Petitclerc E, Wong MK, McMahon GA, Brooks PC, Lawrence DA (2001) Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 276:8135–8141PubMedGoogle Scholar
  61. 61.
    Bacharach E, Itin A, Keshet E (1992) In vivo patterns of expression of urokinase and its inhibitor PAI-1 suggest a concerted role in regulating physiological angiogenesis. Proc Natl Acad Sci U S A 89:10686–10690PubMedCentralPubMedGoogle Scholar
  62. 62.
    Bajou K, Peng H, Laug WE, Maillard C, Noel A, Foidart JM, Martial JA, DeClerck YA (2008) Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14:324–334PubMedCentralPubMedGoogle Scholar
  63. 63.
    Stack MS, Gately S, Bafetti LM, Enghild J, Soff GA (1999) Angiostatin inhibitits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation. Biochem J 340:77–84PubMedGoogle Scholar
  64. 64.
    Gately S, Twardowski P, Stack MS, Cundiff DL, Grella D, Castellino FJ, Enghild J, Kwaan HC, Lee F, Kramer RA, Volpert O, Bouck N, Soff GA (1997) The mechanism of cancer mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci U S A 94:10868–10872PubMedCentralPubMedGoogle Scholar
  65. 65.
    Ramchandran R, Dhanabal M, Volk R, Waterman MJ, Segal M, Lu H, Knelbelmann B, Sukhatme VP (1999) Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem Biophys Res Commun 255:735–739PubMedGoogle Scholar
  66. 66.
    Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R (2000) Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 60:2520–2526PubMedGoogle Scholar
  67. 67.
    Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R (2000) Canstatin, a novel matrix derived inhibitor of angiogenesis and tumor growth. J Biol Chem 275:1209–1215PubMedGoogle Scholar
  68. 68.
    Maeshima Y, Manfredi M, Reimer C, Holthaus KA, Hopfer H, Chandamuri BR, Kharbanda S, Kalluri R (2001) Identification of the antiangiogenic site within vascular basement membrane-derived tumstatin. J Biol Chem 276:15240–15248PubMedGoogle Scholar
  69. 69.
    O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J (1999) Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 285:1926–1928PubMedGoogle Scholar
  70. 70.
    Pike SE, Yao L, Jones KD, Cherney B, Appella E, Sakaguchi K, Nakhasi H, Teruya-Feldstein J, Wirth P, Gupta G, Tosato G (1998) Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J Exp Med 188:2349–2356PubMedCentralPubMedGoogle Scholar
  71. 71.
    Colman RW, Jameson BA, Lin Y, Johnson D, Mousa SA (2000) Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood 95:543–550PubMedGoogle Scholar
  72. 72.
    Degryse B, Sier CF, Resnati M, Conese M, Blasi F (2001) PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor. FEBS Lett 505:249–254PubMedGoogle Scholar
  73. 73.
    McMahon GA, Petitclerc E, Stefansson S, Smith E, Wong MK, Westrick RJ, Ginsburg D, Brooks PC, Lawrence DA (2001) Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem 276:33964–33968PubMedGoogle Scholar
  74. 74.
    Loskutoff DJ, Curriden SA, Hu G, Deng G (1999) Regulation of cell adhesion by PAI-1. APMIS 107:54–61PubMedGoogle Scholar
  75. 75.
    Soff GA, Sanderowitz J, Gately S, Verrusio E, Weiss I, Brem S, Kwaan HC (1995) Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest 96:2593–2600PubMedCentralPubMedGoogle Scholar
  76. 76.
    Chao J, Tillman DM, Wang MY, Margolius HS, Chao L (1986) Identification of a new tissue-kallikrein binding protein. Biochem J 239:325–331PubMedGoogle Scholar
  77. 77.
    Chao J, Chai KX, Chen LM, Xiong W, Chao S, Woodley-Miller C, Chao L (1990) Tissue kallikrein-binding protein is a serpin, I: purification, characterization, and distribution in normotensive and spontaneously hypertensive rats. J Biol Chem 265:16394–16401PubMedGoogle Scholar
  78. 78.
    Chen LM, Ma JX, Liang YM, Chao L, Chao J (1996) Tissue kallikrein-binding protein reduces blood pressure in transgenic mice. J Biol Chem 271:27590–27594PubMedGoogle Scholar
  79. 79.
    Chen LM, Chao L, Chao J (1997) Beneficial effects of kallikrein-binding protein in transgenic mice during endotoxic shock. Life Sci 60:1431–1436PubMedGoogle Scholar
  80. 80.
    Chao J, Stallone JN, Liang YM, Chen LM, Chao L (1997) Kallistatin is a potent new vasodilator. J Clin Invest 100:11–17PubMedCentralPubMedGoogle Scholar
  81. 81.
    Wolf WC, Harley RA, Sluce D, Chao L, Chao J (1999) Localization and expression of tissue kallikrein and kallistatin in human blood vessels. J Histochem Cytochem 47:221–228PubMedGoogle Scholar
  82. 82.
    Miao RQ, Agata J, Chao L, Chao J (2002) Kallistatin is new inhibitor of angiogenesis and tumor growth. Blood 100:3245–3252PubMedGoogle Scholar
  83. 83.
    Miao RQ, Chen V, Chao L, Chao J (2003) Structural elements of kallistatin required for inhibition of angiogenesis. Am J Physiol Cell Physiol 284:C1604–C1613PubMedGoogle Scholar
  84. 84.
    Suzuki K (2008) The multi-functional serpin, protein C inhibitor: beyond thrombosis and hemostasis. J Thromb Haemost 6:2017–2026PubMedGoogle Scholar
  85. 85.
    Asanuma K, Yoshikawa T, Hayashi T, Akita N, Nakagawa N, Hamada Y, Nishioka J, Kamada H, Gabazza EC, Ido M, Uchida A, Suzuki K (2007) Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity. Int J Cancer 121:955–965PubMedGoogle Scholar
  86. 86.
    Celerier J, Cruz A, Lamande N, Gasc JM, Corvol P (2002) Angiotensinogen and its cleaved derivatives inhibit angiogenesis. Hypertension 39:224–228PubMedGoogle Scholar
  87. 87.
    Sheng S (2006) A role of novel serpin maspin in tumor progression: the divergence revealed through efforts to converge. J Cell Physiol 209:631–635PubMedGoogle Scholar
  88. 88.
    Cher ML, Biliran HR Jr, Bhagat S, Meng Y, Che M, Lockett J, Abrams J, Fridman R, Zachareas M, Sheng S (2003) Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis. Proc Natl Acad Sci U S A 100:7847–7852PubMedCentralPubMedGoogle Scholar
  89. 89.
    Biliran H Jr, Sheng S (2001) Pleiotrophic inhibition of pericellular urokinase-type plasminogen activator system by endogenous tumor suppressive maspin. Cancer Res 61:8676–8682PubMedGoogle Scholar
  90. 90.
    McGowen R, Biliran H Jr, Sager R, Sheng S (2000) The surface of prostate carcinoma DU145 cells mediates the inhibition of urokinase-type plasminogen activator by maspin. Cancer Res 60:4771–4778PubMedGoogle Scholar
  91. 91.
    Frey A, Soubani AO, Adam AK, Sheng S, Pass HI, Lonardo F (2009) Nuclear, compared with combined nuclear and cytoplasmic expression of maspin, is linked in lung adenocarcinoma to reduced VEGF-A levels and in Stage I, improved survival. Histopathology 54:590–597PubMedCentralPubMedGoogle Scholar
  92. 92.
    Cella N, Contreras A, Latha K, Rosen JM, Zhang M (2006) Maspin is associated with beta1 integrin regulating cell adhesion in mammary epithelial cells. FASEB J 20:1510–1512PubMedGoogle Scholar
  93. 93.
    Yin S, Lockett J, Meng Y, Biliran H Jr, Blouse GE, Li X et al (2006) Maspin retards cell detachment via a novel interaction with the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system. Cancer Res 66:4173–4181PubMedGoogle Scholar
  94. 94.
    Zhang M, Volpert O, Shi YH, Bouck N (2000) Maspin is an angiogenesis inhibitor. Nat Med 6:196–199PubMedGoogle Scholar
  95. 95.
    Azhar A, Singh P, Rashid Q, Naseem A, Khan MS, Jairajpuri MA (2013) Antiangiogenic function of antithrombin is dependent on its conformational variation: implication for other serpins. Protein Pept Lett 20(4):403–411PubMedGoogle Scholar
  96. 96.
    O’Reilly MS (2007) Antiangiogenic antithrombin. Semin Thromb Hemost 33:660–666PubMedGoogle Scholar
  97. 97.
    Eaton DL, Baker JB (1993) Evidence that a variety of cultured cells secrete protease nexin and produce a distinct cytoplasmic serine protease binding factor. J Cell Physiol 117:175–182Google Scholar
  98. 98.
    Baker JB, Low DA, Simmer RL, Cunningham DD (1980) Protease-nexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Cell 21:37–45PubMedGoogle Scholar
  99. 99.
    Richard B et al (2004) Protease nexin-1: a cellular serpin down-regulated by thrombin in rat aortic smooth muscle cells. J Cell Physiol 201:138–145PubMedGoogle Scholar
  100. 100.
    Bouton MC et al (2007) Protease nexin-1 interacts with thrombomodulin and modulates its anticoagulant effect. Circ Res 100:1174–1181PubMedGoogle Scholar
  101. 101.
    Boulaftali Y et al (2010) Anticoagulant and antithrombotic properties of platelet protease nexin-1. Blood 115:97–106PubMedGoogle Scholar
  102. 102.
    Selbonne S, Azibani F, Iatmanen S, Boulaftali Y, Richard B, Jandrot-Perrus M, Bouton MC, Arocas V (2012) In vitro and in vivo antiangiogenic properties of the serpin protease nexin-1. Mol Cell 32:496–505Google Scholar
  103. 103.
    Phung M, Dass CR (2006) In-vitro and in-vivo assays for angiogenesis-modulating drug discovery and development. J Pharm Pharmacol 58:153–160PubMedGoogle Scholar
  104. 104.
    Kawaguchi T, Yamagishi SI, Sata M (2010) Structure-function relationships of PEDF. Curr Mol Med 10:302–311PubMedGoogle Scholar
  105. 105.
    Bouck N (2002) PEDF: anti-angiogenic guardian of ocular function. Trends Mol Med 8:330–334PubMedGoogle Scholar
  106. 106.
    Elayappan B, Ravinarayannan H, Pasha SP, Lee KJ, Gurunathan S (2009) PEDF inhibits VEGF- and EPO-induced angiogenesis in retinal endothelial cells through interruption of P13K/Akt phosphorylation. Angiogenesis 12:313–324PubMedGoogle Scholar
  107. 107.
    Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP (2007) PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilican vein endothelial cells. Cardiovasc Res 76:213–223PubMedGoogle Scholar
  108. 108.
    Yang H, Cheng R, Liu G et al (2009) PEDF inhibits growth of retinoblastoma by anti-angiogenic activity. Cancer Sci 100:2419–2425PubMedGoogle Scholar
  109. 109.
    Cai J, Jiang WG, Grant MB, Boulton M (2006) Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellular proteolysis of vascular endothelial growth factor receptor-1. J Biol Chem 281:3604–3613PubMedGoogle Scholar
  110. 110.
    Ek ET, Dass C, Contreras KG, Choong PF (2007) Inhibition of orthotopic osteosarcoma growth and metastasis by multitargeted antitumor activities of pigment epithelium-derived factor. Clin Exp Metastasis 24:93–110PubMedGoogle Scholar
  111. 111.
    Manalo KB, Choong PFM, Dass CR (2011) Pigment epithelium-derived factor as an impending therapeutic agent against vascular epithelial growth factor-driven tumor-angiogenesis. Mol Carcinog 50:67–72PubMedGoogle Scholar
  112. 112.
    North S, Moenner M, Bikfalvi A (2005) Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Lett 218:1–14PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Institute of Medical Biology, Polish Academy of SciencesŁódźPoland
  2. 2.Department of Molecular and Medical BiophysicsMedical University of ŁódźŁódźPoland

Personalised recommendations