Skip to main content
SpringerLink
Log in

The Role of Thrombin in Angiogenesis

  • Chapter
  • First Online:
Thrombin

Abstract

The suggestion of the late Judah Folkman that “solid tumors are angiogenesis-dependent” in the 1970s stimulated a multidisciplinary research effort to understand the complex cascade of events involved in new blood vessel formation under physiological and pathological conditions. A plethora of endogenous modulators of angiogenesis has been identified, and their roles in the molecular and cellular events that mediate and regulate angiogenesis have been proposed. In addition, it has been recognized that besides solid tumors a large number of common diseases such as ocular diseases, inflammation, etc., have as underlying pathology the derangement of angiogenesis. This prompted a major effort of the biotechnology industry to identify targets and develop agents for the so called angiogenesis-based therapies. A brief overview of the regulation of angiogenesis and the clinical applications that have resulted thus far is presented. Furthermore, our finding that thrombin is a potent angiogenic mediator that may play a pivotal role in orchestrating angiogenic factors led us to summarize the recent findings on the role of the coagulation cascade and its components in angiogenesis. Thrombin is a promoter of angiogenesis by activating PAR1 receptors in platelet and endothelial cells. This identifies PAR1 as a target for inhibiting angiogenesis with potential therapeutic applications. In addition, thrombin plays a role in promoting angiogenesis by PAR1-independent mechanisms. Through its RGD sequence, thrombin serves as an adhesive and aptotactic factor for endothelial cells . Thrombin is a potent antiapoptotic factor for endothelial cells, pointing to a novel role of thrombin in vascular protection and integrity. The implications of these findings in the overall regulation of angiogenesis and their possible significance in pathological states are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abe, K., Shoji, M., Chen, J., Bierhaus, A., Danave, I., Micko, C., Casper, K., Dillehay, D.L., Nawroth, P.P., and Rickles, F.R. 1999. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor. Proc. Natl. Acad. Sci. USA 96: 8663–8668.

    Article  PubMed  CAS  Google Scholar 

  • Amirkhosravi, A., Meyer, T., Amaya, M., Davila, M., Mousa, S.A., Robson, T., and Francis, J.L. 2007. The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin. Thromb. Hemost. 33: 643–652.

    Article  PubMed  CAS  Google Scholar 

  • Asahara, T. and Kawamoto, A. 2004. Endothelial progenitor cells for postnatal vasculogenesis. Am. J. Physiol. Cell Physiol. 287: C572–C579.

    Article  PubMed  CAS  Google Scholar 

  • Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G., and Isner, J.M. 1997. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967.

    Article  PubMed  CAS  Google Scholar 

  • Asanuma, K., Yoshikawa, T., Hayashi, T., Akita, N., Nakagawa, N., Hamada, Y., Nishioka, J., Kamada, H., Gobazza, E.C., Ido, M., Ushida, A., and Susuki, K. 2007. Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity. Int. J. Cancer 121: 955–965.

    Article  PubMed  CAS  Google Scholar 

  • Bar-Shavit, R., Eldor, A., and Vlodavsky, I. 1989. Binding of thrombin to subendothelial extracellular matrix: protection and expression of functional properties. J. Clin. Invest. 84: 1096–1104.

    Article  PubMed  CAS  Google Scholar 

  • BelAida, R.S., Djordjevic, T., Bonello, S., Flugel, D., Hess, J., Kietzmann, T., and Gorlach, A. 2004. Redox-sensitive regulation of HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells. Biol. Chem. 385: 249–257.

    Google Scholar 

  • Belting, M., Dorrell, M.I., Sandgren, S., Aguilar, E., Ahamed, J., Dorfleutner, A., Carmeliet, P., Mueller, B.M., Friedlander, M., and Ruf, W. 2004. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat. Med. 10: 502–509.

    Article  PubMed  CAS  Google Scholar 

  • Bergers, B. and Song, S. 2005. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. 7: 452–464.

    Article  PubMed  CAS  Google Scholar 

  • Boire, A., Covic, L., Agarwal, A., Jacques, S., Sherifi, S., and Kuliopulos, A. 2005. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120: 303–313.

    Article  PubMed  CAS  Google Scholar 

  • Brill, A., Dashevsky, O., Rivo, J., Gozal, Y., and Varon, D. 2005. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc. Res. 67: 30–38.

    Article  PubMed  CAS  Google Scholar 

  • Browder, T., Folkman, J., and Pirie-Shepherd, S. 2000. The hemostatic system as a regulator of angiogenesis. J. Biol. Chem. 275: 1521–1524.

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet, P. 2005. Angiogenesis in life, disease and medicine. Nature 438: 932–936.

    Article  PubMed  CAS  Google Scholar 

  • Caunt, M., Hu, L., Tang, T., Brooks, P., Ibrahim, S., and Karpatkin, S. 2006. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res. 66: 4125–4132.

    Article  PubMed  CAS  Google Scholar 

  • Caunt, M., Huang, Y., Brooks, P., and Karpatkin, S. 2003. Thrombin induces neoangiogenesis in the chick chorioallontoic membrane. J. Thromb. Haemost. 1: 2097–2102.

    Article  PubMed  CAS  Google Scholar 

  • Chen, D., Abrahams, J.M., Smith, L.M., McVey, J.H., Lechler, R.I., and Dorling, A. 2008. Regenerative repair after endoluminal injury in mice with specific antagonism of protease activated receptors on CD34 + vascular progenitors. Blood 111: 4155–4164.

    Article  PubMed  CAS  Google Scholar 

  • Clark, R.A., Tonnesen, M.G., Gailit, J., and Cheresh, D.A. 1996. Transient functional expression of ανβ3 on vascular cells during wound repair. Am. J. Pathol. 148: 1407–1421.

    PubMed  CAS  Google Scholar 

  • Coultas, L., Chawengsaksophak, K., and Rossant, J. 2005. Endothelial cells and VEGF in vascular development. Nature 438: 937–945.

    Article  PubMed  CAS  Google Scholar 

  • Dallabrida, S.M., De Sousa, M.A., and Farrell, D.H. 2000. Expression of antisense to integrin subunit β3 inhibits microvascular endothelial cell capillary tube formation in fibrin. J. Biol. Chem. 275: 32281–32288.

    Article  PubMed  CAS  Google Scholar 

  • Darland, D.C. and D’Amore, P.A. 1999. Blood vessel maturation: vascular development comes of age. J. Clin. Invest. 103: 157–158.

    Article  Google Scholar 

  • Daubie, V., Pochet, R., Houard, S., and Philippart, P. 2007. Tissue factor: a mini-review. J. Tissue Eng. Regen. Med. 1: 161–169.

    Article  PubMed  CAS  Google Scholar 

  • De Paula, E.V., Nascimento, M.C., Ramos, C.D., Ozelo, M.C., Machado, T.F., Guillaumon, A.T., Arruba, V.R., and Annichino-Bizzacchi, J.M. 2006. Early in vivo anticoagulation inhibits the angiogenic response following hindlimb ischemia in a rodent model. Thromb. Haemost. 96: 68–72.

    PubMed  CAS  Google Scholar 

  • Dimitropoulou, C., Maragoudakis, M.E., and Konerding, M.A. 2002. Effects of thrombin and of the phospholipase C inhibitor, D609, on the vascularity of the chick chorioallontoic membrane. Gen. Pharmacol. 35: 241–247.

    Google Scholar 

  • Dome, B., Hendrix, M.J., Paku, S., Tovari, J., and Timar,2007. Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am. J. Pathol. 70: 1–15.

    Article  CAS  Google Scholar 

  • Dupuy, E., Habib, A., Lebret, M., Yang, R., Levy-Toledano, S., and Tobelem, G. 2003. Thrombin induces angiogenesis and vascular endothelial growth factor expression in human endothelial cells: possible relevance to HIF-I alpha. J. Thromb. Haemost. 1: 1096–1102.

    Article  PubMed  CAS  Google Scholar 

  • Dvorak, H.F. 2005. Angiogenesis: update 2005. J. Thromb. Haemost. 3: 1835–1842.

    Article  PubMed  CAS  Google Scholar 

  • Dvorak, H.F., Harvey, V.S., Estrella, P., Brown, L.F., McDonagh, J., and Dvorak, A.M. 1987. Fibrin containing gells induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab. Invest. 57: 673–686.

    PubMed  CAS  Google Scholar 

  • Eming, S.A., Brachvogel, B., Odorisio, T., and Koch, M. 2007. Regulation of angiogenesis: wound healing as a model. Prog. Histochem. Cytochem. 42: 115–170.

    Article  PubMed  CAS  Google Scholar 

  • Esmon, C.T. 2006. Inflammation and the activated protein C anticoagulant pathway. Semin. Thromb. Haemost. 32: 49–60.

    Article  CAS  Google Scholar 

  • Falanga, A., Marchetti, M., Vignoli, A., and Balducci, D. 2003. Clotting mechanisms and cancer: implications in thrombus formation and tumor progression. Clin. Adv. Hematol. Oncol. 1: 673–678.

    PubMed  Google Scholar 

  • Fernandez, P.M., Patierno, S.R., and Rickles, F.R. 2004. Tissue factor and fibrin in tumor angiogenesis. Semin. Thromb. Hemost. 30: 31–44.

    PubMed  CAS  Google Scholar 

  • Fernandez-Patron, C., Zhang, Y., Radomski, M.W., Hollenberg, M.D., and Davidge, S.T. 1999. Rapid release of matrix metalloproteinase (MMP)-2 by thrombin in the rat aorta: modulation by protein tyrosine kinase/phosphatase. Thromb. Haemost. 82: 1353–1357.

    PubMed  CAS  Google Scholar 

  • Ferrara, N. 2004. Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 25: 581–611.

    Article  PubMed  CAS  Google Scholar 

  • Ferrara, N. and Kerbel, R.S. 2005. Angiogenesis as a therapeutic target. Nature 438: 967–974.

    Article  PubMed  CAS  Google Scholar 

  • Folkman, J. 2006. Angiogenesis. Annu. Rev. Med. 57: 1–18.

    Article  PubMed  CAS  Google Scholar 

  • Freyssinet, J.M. 2003. Cellular microparticles: what are they bad or good for? J. Thromb. Haemost. 1: 1655–1662.

    Article  PubMed  CAS  Google Scholar 

  • Friesel, R. and Maciag, T. 1999. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling. Thromb. Haemost. 82: 748–754.

    PubMed  CAS  Google Scholar 

  • Gang, U.C. and Hassid, A. 1989. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J. Clin. Invest. 83: 1774–1777.

    Article  Google Scholar 

  • Good, D.J., Polverini, P.J., Rastinejad, F., Le Beau, M.M., Lemons, R.S., Frazier, W.A., and Bouck, N.P. 1990. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc. Natl. Acad. Sci. USA 87: 6624–6628.

    Article  PubMed  CAS  Google Scholar 

  • Gorlach, A., Diebold, I., Schini-Kerth, V.B., Berchner-Pfannschmidt, U., Roth, U., Brandes, R.P., Kietzmann, T., and Busse, R. 2001. Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: role of p22phox.-containing NAPDH oxidase Circ. Res. 89: 47–54.

    Article  PubMed  CAS  Google Scholar 

  • Gragoudas, E.S., Adamis, A.P., Cunningham, E.T., Jr., Feinsod, M., and Guyer, D.R. 2004. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351: 2805–2816.

    Article  PubMed  CAS  Google Scholar 

  • Guan, M., Jin, J., Su, B., Liu, W.W., and Lu, Y. 2002. Tissue factor expression and angiogenesis in human glioma. Clin. Biochem. 35: 321–325.

    Article  PubMed  CAS  Google Scholar 

  • Guo, P., Hu, B., Gu, W., Xu, L., Wang, D., Huang, H.J., Cavenee, W.K., and Cheng, S.Y. 2003. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am. J. Pathol. 162: 1083–1093.

    Article  PubMed  CAS  Google Scholar 

  • Haralabopoulos, G.C., Grant, D.S., Klienman, H.K., and Maragoudakis, M.E. 1997. Thrombin promotes endothelial cell alignment in matrigel in vitro and angiogenesis in vivo. Am. J. Physiol. Cell Physiol. 273: C239–C242.

    CAS  Google Scholar 

  • Heller, R., Polack, T., Grabner, R., and Till, U. 1999. Nitric oxide inhibits proliferation of human endothelial cells via a mechanism independent of cGMP. Atherosclerosis 144: 49–57.

    Article  PubMed  CAS  Google Scholar 

  • Hershey, J.C., Baskin, E.P., Glass, J.D., Hartman, H.A., Gilberto, D.B., and Rogers, I.T. 2001. Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis. Cardiovasc. Res. 49: 618–625.

    Article  PubMed  CAS  Google Scholar 

  • Huang, Y.-Q., Li, J.-J., Hu, L., Lee, M., and Karpatkin, S. 2001. Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes. Thromb. Haemost. 86: 1094–1098.

    PubMed  CAS  Google Scholar 

  • Huang, Y.-Q., Hu, L., Lee, M., and Karpatkin, S. 2002. Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells. Blood 99: 1646–1650.

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz, H., Fehrenbacher, L., Novotny, N., Cartwright, T., Hainsworth, J., Hein, W., Berlin, J., Baron, A., Griffing, S., Holmqren, E., Ferrara, N., Fyfe, G., Rogers, B., Ross, R., and Kabbinavar, F. 2004. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350: 2335–2342.

    Article  PubMed  CAS  Google Scholar 

  • Idris, N.M., Haider, H.H., and Sim, E.K.W. 2004. Therapeutic angiogenesis for treatment of peripheral vascular disease. Growth Factors 22: 269–279.

    Article  PubMed  CAS  Google Scholar 

  • Itoh, T., Tanioka, M., Yoshida, H., Yoshika, T., Nischimoto, H., and Itohara, S. 1998. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58: 1048–1051.

    PubMed  CAS  Google Scholar 

  • Ivanciu, L., Gerard, R.D., Tang, H., Lupu, F., and Lupu, C. 2007. Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 27: 310–316.

    Article  PubMed  CAS  Google Scholar 

  • Janowska-Wieczorek, A., Wysoczynski, M., Kijowski, J., Marquez-Curtis, L., Machalinski, B., Ratajczak, J., and Ratajczak, M.Z. 2005. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer 113: 752–760.

    Article  PubMed  CAS  Google Scholar 

  • Kim, T.H., Kim, E., Yoon, D., Kim, J., Rhim, T.Y., and Kim, S.S. 2002. Recombinant human prothrombin kringles have potent anti-angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases. Angiogenesis 5: 191–201.

    Article  PubMed  CAS  Google Scholar 

  • Kisucka, J., Butterfield, C.E., Duda, D.G., Eichenberger, S.C., Saffaripour, S., Ware, J., Ruggeri, Z.M., Jain, R.K., Folkman, J., and Wagner, D.D. 2006. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc. Natl. Acad. Sci. USA 103: 855–860.

    Article  PubMed  CAS  Google Scholar 

  • Koolwijk, P., van Erck, M.G., de Vree, W.J., Vermeer, M.A., Weich, H.A., Hanemaaijer, R., and van Hinsberg, V.W. 1996. Cooperative effect of TNF-alpha, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity. J. Cell Biol. 132: 1177–1188.

    Article  PubMed  CAS  Google Scholar 

  • Kopp, H.G., Ramos, C.A., and Rafii, S. 2006. Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization ofg tumor and isdchemic tissue. Curr. Opin. Hematol. 13: 175–181.

    Article  PubMed  CAS  Google Scholar 

  • Kubes, P., Susuki, M., and Gramger, D.N. 1991. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc. Natl. Acad. Sci. USA 88: 4651–4655.

    Article  PubMed  CAS  Google Scholar 

  • Laurens, N., Koolwijk, P., and Maat, M.P.M. 2006. Fibrin structure and wound healing. J Thromb. Haemost. 4: 932–939.

    Article  PubMed  CAS  Google Scholar 

  • Lee, T.H., Rhim, T., and Kim, S.S. 1998. Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells. J. Biol. Chem. 273: 28805–28812.

    Article  PubMed  CAS  Google Scholar 

  • Lidington, E.A., Haskard, D.O., and Mason, J.C. 2000. Induction of decay-accelerating factor by thrombin through a protease-activated receptor 1 and protein kinase-dependent pathway protects vascular endothelial cells from complement-mediated injury. Blood 96: 2784–2792.

    PubMed  CAS  Google Scholar 

  • Lindhal, P., Johansson, B.E., Leveen, P., and Betsholtz, C. 1997. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277: 242–245.

    Article  Google Scholar 

  • Liou, J.Y., Lee, S., Ghelani, D., Matijevic-Aleksic, N., and Wu, K.K. 2006. Protection of endothelial survival by peroxisome proliferators-activated receptor-{delta} mediated 14-3-3 upregulation. Arterioscler. Thromb. Vasc. Biol. 26: 1481–1487.

    Article  PubMed  CAS  Google Scholar 

  • Liu, H.M., Wang, D.L., and Liu, C.Y. 1990. Interactions between fibrin, collagen and endothelial cells in angiogenesis. Adv. Exp. Med. Biol. 281: 319–331.

    Article  PubMed  CAS  Google Scholar 

  • Ma, L., Perini, R., McKnight, W., Klein, A., Hollenberg, M.D., and Wallace, J.L. 2005. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc. Natl. Acad. Sci. USA 102: 216–220.

    Article  PubMed  CAS  Google Scholar 

  • Macfarlane, S.R., Seatter, M.J., Kanke, T., Hunter, G.D., and Plevin, R. 2001. Proteinase-activated receptors. Pharmacol. Rev. 53: 245–282.

    PubMed  CAS  Google Scholar 

  • Maisonpierre, P.C., Suri, C., Jones, P.F., Bartunkova, S., Wiegand, S.J., Radziejewski, C., Compton, D., McClain, J., Aldrich, T.H., Papadopoulos, N., Daly, T.J., Davis, S., Sato, T.N., and Yancopoulos, G.D. 1997. Angiopoietin-2, a natural antagonist for Tie-2 that disrupts in vivo angiogenesis. Science 277: 55–60.

    Article  PubMed  CAS  Google Scholar 

  • Maragoudakis, M.E., Missirlis, E., Karakioulakis, G., Sarmonika, M., Bastakis, M., and Tsopanoglou, N.E. 1993. Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with antitumor properties. Kidney Int. 43: 147–150.

    Article  PubMed  CAS  Google Scholar 

  • Martinez, J., Ferber, A., Bach, T.L., and Yaen, C.H. 2001. Interaction of fibrin with VE-cadherin. Ann. N. Y. Acad. Sci. 936: 386–405.

    Article  PubMed  CAS  Google Scholar 

  • Martorell, L., Martionez-Gonzalez, J., Crespo, J., Calvayrac, O., and Badimon, L. 2007. Neuro-derived orphan receptor-1 (NOR-1) is induced by thrombin and mediates endothelial cell growth. J. Thromb. Haemost. 5: 1766–1773.

    Article  PubMed  CAS  Google Scholar 

  • Martorell, L., Martinez-Gonzalez, J., Rodriguez, C., Gentile, M., Calvayrac, O., and Badimon, L. 2008. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb. Haemost. 99: 305–315.

    PubMed  CAS  Google Scholar 

  • Medved, L., Tsurupa, G., and Yakovlev, S. 2001. Conformational changes upon conversion of fibrinogen into fibrin: the mechanisms of exposure of cryptic sites. Ann. N. Y. Acad. Sci. 936: 185–204.

    Article  PubMed  CAS  Google Scholar 

  • Mohle, R., Green, D., Moore, M.A., Nachman, R.L., and Rafii, S. 1997. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl. Acad. Sci. USA 94: 663–668.

    Article  PubMed  CAS  Google Scholar 

  • Nakasaki, T., Wada, H., Shigemori, C., Miki, C., Gabazza, E.C., Nobori, T., Nakamura, S., and Shiku, H. 2002. Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer. Am. J. Hematol. 69: 247–254.

    Article  PubMed  CAS  Google Scholar 

  • Neaud, V., Duplantier, J.G., Mazzocco, C., Kisiel, W., and Rosenbaum, J. 2004. Thrombin up-regulates tissue factor pathway inhibitor-2 synthesis through a cyclooxygenase-2-dependent, epidermal growth factor receptor-independent mechanism. J. Biol. Chem. 279: 5200–5206.

    Article  PubMed  CAS  Google Scholar 

  • Nyberg, P., Xie, L., and Kalluri, R. 2005. Endogenous inhibitors of angiogenesis. Cancer Res. 65: 3967–3979.

    Article  PubMed  CAS  Google Scholar 

  • Oliner, J., Min, H., Leal, J., Xu, D., Rao, S., You, E., Tang, X., Kim, H., Meyer, S., et al. 2004. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6: 507–516.

    Article  PubMed  CAS  Google Scholar 

  • Olivot, J.-M., Estebanell, E., Lafay, M., Brohard, B., Aiach, M., and Rendu, F. 2001. Thrombomodulin prolongs thrombin-induced extracellular signal-regulated kinase phosphorylation and nuclear retention in endothelial cells. Circ. Res. 88: 681–687.

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly, M.S. 2007. Antiangiogenic antithrombin. Semin. Thromb. Hemost. 33: 660–666.

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly, M.S., Pirie-Shepherd, S., Lane, W.S., and Folkman, J. 1999. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 285: 1926–1928.

    Article  PubMed  Google Scholar 

  • Papaconstantinou, M.E., Carrell, C.J., Pineda, A.O., Bobofchak, K.M., Mathews, F.S., Flordellis, C.S., Maragoudakis, M.E., Tsopanoglou, N.E., and Di Cera, E. 2005. Thrombin functions through its RGD sequence in a non-canonical conformation. J. Biol. Chem. 280: 29393–29396.

    Article  PubMed  CAS  Google Scholar 

  • Pipili-Synetos, E., Papadimitriou, E., and Maragoudakis, M.E. 1998. Evidence that platelets promote tube formation by endothelial cells on matrigel. Br. J. Pharmacol. 125: 1252–1257.

    Article  PubMed  CAS  Google Scholar 

  • Pizurki, L., Zhou, Z., Glynos, K., Roussos, C., and Papapetropoulos, A. 2003. Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production. Br. J. Pharmacol. 139: 329–336.

    Article  PubMed  CAS  Google Scholar 

  • Poschl, E., Schlotzer-Schrehardt, U., Brachvogel, B., Saito, K., Ninomiya, Y., and Mayer, U. 2004. Collagen IV is essential for basement membrane stability but early dispensable for initiation of its assemply during early development. Development 131: 1619–1628.

    Article  PubMed  CAS  Google Scholar 

  • Rhee, J.S., Black, M., Schubert, U., Fischer, S., Morgenstern, E., Hammes, H.P., and Preissner, K.T. 2004. The functional role of blood platelet components in angiogenesis. Thromb. Haemost. 92: 394–402.

    PubMed  CAS  Google Scholar 

  • Rickles, F.R., Patierno, S., and Fernandez, P.M. 2003. Tissue factor, thrombin and cancer. Chest 124: 58S–68S.

    Article  PubMed  CAS  Google Scholar 

  • Risau, W. 1997. Mechanisms of angiogenesis. Nature 386: 671–674.

    Article  PubMed  CAS  Google Scholar 

  • Roy, R., Zhang, B., and Moses, M.A. 2006. Making the cut: protease-mediated regulation of angiogenesis. Exp. Cell Res. 312: 608–622.

    Article  PubMed  CAS  Google Scholar 

  • Ruegg, C. and Mariotti, A. 2003. Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell. Mol. Life Sci. 60: 1135–1157.

    PubMed  CAS  Google Scholar 

  • Sahni, A. and Francis, C.W. 2000. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood 96: 3772–3778.

    PubMed  CAS  Google Scholar 

  • Sahni, A., Sporn, L.A., and Francis, C.W. 1999. Potentiation of endothelial cell proliferation by fibrin(ogen)-bound fibroblast growth factor-2. J. Biol. Chem. 274: 14936–14941.

    Article  PubMed  CAS  Google Scholar 

  • Sahni, A., Baker, C.A., Sporn, L.A., and Francis, C.W. 2000. Fibrinogen and fibrin protect fibroblast growth factor-2 from proteolytic degradation. Thromb. Haemost. 83: 736–741.

    PubMed  CAS  Google Scholar 

  • Sawada, M., Miyake, S., Ahdama, S., Matsubara, O., Masuda, S., Yakumaru, K., and Yoshizawa, Y. 1999. Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis. Br. J. Cancer 79: 472–477.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, H.H. and Walter, U. 1994. NO at work. Cell 78: 919–925.

    Article  PubMed  CAS  Google Scholar 

  • Serini, G., Napione, L., Arese, M., and Bussolino, F. 2008. Besides the adhesion: new perspectives of integrins functions in angiogenesis. Cardiovasc. Res. 78: 213–222.

    Article  PubMed  CAS  Google Scholar 

  • Shirotani, M., Yui, Y., Hattori, R., and Kawai, C. 1991. U-61,431F, a stable prostacyclin analogue, inhibits the proliferation of bovine vascular smooth muscle cells with little antiproliferative effect on endothelial cells. Prostaglandins 41: 97–110.

    PubMed  CAS  Google Scholar 

  • Sierko, E., Wojtukiewicz, M.Z., and Kisiel, W. 2007. The role of tissue factor pathway inhibitor-2. Semin. Thromb. Haemost. 33: 653–659.

    Article  CAS  Google Scholar 

  • Simons, M. 2005. Angiogenesis: where do we stand now? Circulation 111: 1556–1566.

    Article  PubMed  Google Scholar 

  • Smadja, D.M., Bieche, I., Uzan, G., Bompais, H., Muller, L., Boisson-Vidal, C., Vidaud, M., Aiach, M., and Gaussem, P. 2005. PAR-1 activation on human late endothelial progenitor cells enhances angiogenesis in vitro with upregulation of the SDF-1/CXCR4 system. Arteriol. Thromb. Vasc. Biol. 25: 2321–2327.

    Article  CAS  Google Scholar 

  • Smadja, D.M., Laurendeau, I., Avignon, C., Vidaud, M., Aiach, M., and Gaussem, P. 2006. The angiopoietin pathway is modulated by PAR-1 activation on human endothelial progenitor cells. J. Thromb. Haemost. 4: 2051–2058.

    Article  PubMed  CAS  Google Scholar 

  • Smadja, D.M., Basire, A., Amelot, A., Conte, A., Bieche, I., Le Bonniec, B.F., Aiach, M., and Gaussem, P. 2008. Thrombin bound to a fibrin clot confers angiogenic and haemostatic properties on endothelial progenitor cells. J. Cell. Mol. Med. 12: 975–986.

    Article  PubMed  CAS  Google Scholar 

  • Stupp, R. and Ruegg, C. 2007. Integrin inhibitors reaching the clinic. J. Clin. Oncol. 25: 1637–1638.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki, K. and Hayashi, T. 2007. Protein C and its inhibitor in malignancy. Semin. Thromb. Haemost. 33: 667–672.

    Article  CAS  Google Scholar 

  • Tarzami, S.T., Wang, G., Li, W., Green, L., and Singh, J.P. 2005. Thrombin and PAR-1 stimulate differentiation of bone marrow-derived endothelial progenitor cells. J. Thromb. Haemost. 4: 656–663.

    Article  Google Scholar 

  • Thompson, W.D., Smith, E.B., Stirk, C.M., Marshall, F.I., Stout, A.J., and Kocchar, A. 1992. Angiogenic activity of fibrin degradation products is located in fibrin fragment E. J. Pathol. 168: 47–53.

    Article  PubMed  CAS  Google Scholar 

  • Tsopanoglou, N.E. and Maragoudakis, M.E. 1998. On the mechanism of thrombin-induced angiogenesis: inhibition of attachment of endothelial cells on basement membrane components. Angiogenesis 1: 192–200.

    Article  PubMed  Google Scholar 

  • Tsopanoglou, N.E. and Maragoudakis, M.E. 1999. On the mechanism of thrombin-induced angiogenesis: potentiation of vascular endothelial growth factor activity on the endothelial cells by up-regulation of its receptors. J. Biol. Chem. 274: 23969–23976.

    Article  PubMed  CAS  Google Scholar 

  • Tsopanoglou, N.E. and Maragoudakis, M.E. 2004. Role of thrombin in angiogenesis and tumor progression. Semin. Thromb. Haemost. 30: 63–69.

    Article  CAS  Google Scholar 

  • Tsopanoglou, N.E., Pipili-Synetos, E., and Maragoudakis, M.E. 1993. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation. Am. J. Physiol. Cell Physiol. 264: C1302–C1307.

    CAS  Google Scholar 

  • Tsopanoglou, N.E., Andriopoulou, P., and Maragoudakis, M.E. 2002. On the mechanism of thrombin-induced angiogenesis: involvement of ανβ3 integrin. Am. J. Physiol. Cell Physiol. 283: C1501–C1510.

    Article  PubMed  CAS  Google Scholar 

  • Tsopanoglou, N.E., Papaconstantinou, M., Flordellis, C.S., and Maragoudakis, M.E. 2004. On the mode of action of thrombin-induced angiogenesis: thrombin peptide, TP508, mediates effects in endothelial cells via ανβ3. Thromb. Haemost. 92: 846–857.

    PubMed  CAS  Google Scholar 

  • Ueno, T., Toi, M., Koike, M., Nakamura, S., and Tominaga, T. 2000. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br. J. Cancer 83: 164–170.

    Article  PubMed  CAS  Google Scholar 

  • Ushiba, M., Okajima, K., Oike, Y., Ito, Y., Fukudome, K., Isobe, H., and Suda, T. 2004. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ. Res. 95: 34–41.

    Article  CAS  Google Scholar 

  • Vale, P.R., Isner, J., and Rosenfield, K. 2001. Therapeutic angiogenesis in critical limb and myocardial ischemia. J. Interv. Cardiol. 14: 511–528.

    Article  PubMed  CAS  Google Scholar 

  • Van de Wouwer, M., Collen, D., and Conway, E.M. 2004. Thrombomodulin-protein C- EPCR system. Integrated to regulate coagulation and inflammation. Arterioscler. Thromb. Vasc. Biol. 24: 1374–1383.

    Article  PubMed  CAS  Google Scholar 

  • Verheul, H.M. and Pinedo, H.M. 2007. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat. Rev. Cancer 7: 475–485.

    Article  PubMed  CAS  Google Scholar 

  • Verheul, H.M., Jorna, A.S., Hoekman, K., Broxterman, H.J., Gebbink, M.F., and Pinedo, H.M. 2000. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 96: 4216–4221.

    PubMed  CAS  Google Scholar 

  • Verheul, H.M.W., Hoekman, K., Luykx-de Bakker, S., Eekman, C.A., Folman, C.C., Broxterman, H.J., and Pinedo, H.M. 1997. Platelet transporter of vascular endothelial growth factor. Clin. Cancer Res. 3: 2187–2190.

    PubMed  CAS  Google Scholar 

  • Versteeg, H.H. and Ruf, W. 2006. Emerging insights in tissue factor dependent signaling events. Semin. Thromb. Haemost. 32: 24–32.

    Article  CAS  Google Scholar 

  • Vu, T.H., Shipley, M., Bergers, G., Bergers, J.E., Helms, J.A., Hanakan, D., Shapiro, S.D., Senior, R.M., and Werb, Z. 1998. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypetrophic chondrocytes. Cell 93: 411–422.

    Article  PubMed  CAS  Google Scholar 

  • Wartiovaara, U., Salven, P., and Mikkola Heta, I. 1998. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb. Haemost. 80: 171–175.

    PubMed  CAS  Google Scholar 

  • Watanabe, K., Hasegawa, Y., Yamashita, H., Shimizu, K., Ding, Y., Abe, M., Ohta, H., Imagawa, K., Hojo, K., Maki, H., Sonoda, H., and Sato, Y. 2004. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J. Clin. Invest. 114: 898–907.

    PubMed  CAS  Google Scholar 

  • Whittle, B.J., Moncada, S., and Vane, J.R. 1978. Comparison of the effects of prostacyclin (PGI2), prostaglandin E1 and D2 on platelet aggregation in different species. Prostaglandins 16: 373–388.

    PubMed  CAS  Google Scholar 

  • Wojtukiewicz, M.Z., Sierko, E., and Rak, J. 2004. Contribution of the hemostatic system to angiogenesis in cancer. Semin. Thromb. Haemost. 30: 5–20.

    Article  CAS  Google Scholar 

  • Xu, Z., Maiti, D., Kisiel, W., and Duh, E.L. 2006. Tissue factor pathway inhibitor-2 is up-regulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26: 2819–2825.

    Article  PubMed  CAS  Google Scholar 

  • Yanamandra, N., Kondraganti, S., Gondi, C.S., Gujivati, M., Olivero, W.C., Dinh, D.H., and Rao, J.S. 2005. Recombinant adeno-associated virus (rAAV) expressing TFPI-2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line. Int. J. Cancer 115: 998–1005.

    Article  PubMed  CAS  Google Scholar 

  • Yancopoulos, G.D., Davis, S., Gale, N.W., Rudge, J.S., Wiegand, S.J., and Holash, J. 2000. Vascular-specific growth factors and blood vessel formation. Nature 407: 242–248.

    Article  PubMed  CAS  Google Scholar 

  • Zania, P., Kritikou, S., Flordellis, C.S., Maragoudakis, M.E., and Tsopanoglou, N.E. 2006. Blockage of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis. J. Pharmacol. Exp. Ther. 318: 246–254.

    Article  PubMed  CAS  Google Scholar 

  • Zania, P., Papaconstantinou, M., Flordellis, C.S., Maragoudakis, M.E., and Tsopanoglou, N.E. 2008. Thrombin mediates mitogenesis and survival of human endothelial cells through distinct mechanisms. Am. J. Physiol Cell Physiol. 294: C1215–C1226.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Y., Deng, Y., Luther, T., Muller, M., Ziegler, R., Waldherr, R., Stern, D.M., and Nawroth, P.P. 1994. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J. Clin. Invest. 94: 1320–1327.

    Article  PubMed  CAS  Google Scholar 

  • Zhou, Z., Apte, S.S., Soininen, R., Cao, R., Baaklini, G.Y., Rauser, R.W., Wong, J., Cao, Y., and Tryggvason, K. 2000. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl. Acad. Sci. USA 97: 4052–4057.

    Article  PubMed  CAS  Google Scholar 

  • Zucker, S., Conner, C., DiMassimo, B.I., Ende, H., Drew, M., Seiki, M., and Bahou, W.F. 1995. Thrombin induces the activation of progelatinase A in vascular endothelial cells. J. Biol. Chem. 270: 23730–23738.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Nikos E. Tsopanoglou, Department of Pharmacology, Medical School, University of Patras, 26500, Patras, Greece

    Nikos E. Tsopanoglou* & Michael E. Maragoudakis

Authors
  1. Nikos E. Tsopanoglou*
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Maragoudakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nikos E. Tsopanoglou* .

Editor information

Editors and Affiliations

  1. Medical School, University of Patras, Patras, Greece

    Michael E. Maragoudakis  & Nikos E. Tsopanoglou  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Tsopanoglou*, N.E., Maragoudakis, M.E. (2009). The Role of Thrombin in Angiogenesis . In: Maragoudakis, M., Tsopanoglou, N. (eds) Thrombin. Springer, New York, NY. https://doi.org/10.1007/978-0-387-09637-7_6

Download citation

Publish with us

Policies and ethics

Search

Navigation