The Hemostatic System as a Regulator of Angiogenesis (2000)

vascular endothelial growth factor basic fibroblast growth factor hepatocyte growth factor platelet factor 4 antithrombin III thrombospondin transforming growth factor-β1 plasminogen activator inhibitor type 1 urokinase-type plasminogen activator high molecular weight kininogen matrix metalloproteinase Angiogenesis is the process of sprouting and configuring new blood vessels from pre-existing blood vessels, whereas the hemostatic system maintains the liquid flow of blood by regulating platelet adherence and fibrin deposition. Both systems normally appear quiescent, yet both systems remain poised for repair of injury. With vessel injury, a rapid sequence of reactions must occur to occlude the vessel wall defect and prevent hemorrhage. Activated platelets link the margins of the defect and form a provisional barrier that is quickly enmeshed with polymerized fibrin. This clot structure initially requires immobilized vascular endothelial cells to anchor the clot and prevent further bleeding. Thereafter, endothelial cells at the clot margins become mobile, dismantling and invading the cross-linked fibrin structure to rebuild a new vessel wall. Although the positive and negative regulators that control the delicate balance of platelet reactivity and fibrin deposition have been elucidated over the past four decades, analogous proteins that control endothelial cell growth and inhibition have only been discovered within the past decade. Hemostasis and angiogenesis are becoming increasingly inter-related. Proteins generated by the hemostatic system coordinate the spatial localization and temporal sequence of clot/endothelial cell stabilization followed by endothelial cell growth and repair of a damaged blood vessel. We focus here on the regulation of angiogenesis during vessel repair mediated by proteins secreted by platelets and derived as cryptic fragments from the coagulation cascade and fibrinolytic system. At the site of vessel injury, adhered platelets secrete both positive and negative regulators of angiogenesis, mainly from internal α-granules. These positive regulators include: vascular endothelial growth factor-A (VEGF-A)1(1.Mohle R. Green D. Moore M.A.S. Nachman R.L. Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets..Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 663-668Crossref PubMed Scopus (640) Google Scholar), VEGF-C (2.Wartiovaara U. Salven P. Mikkola H. Lassila R. Kaukonen J. Joukov V. Orpana A. Ristimaki A. Heikinheimo M. Joensuu H. Aitalo K. Palotie A. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation..Thromb. 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A fibroblast-derived tumor cytotoxic factor/F-TCF (hepatocyte growth factor/HGF) has multiple functions in vitro..Cell Biol. Int. Rep. 1991; 15: 397-408Crossref PubMed Scopus (56) Google Scholar, 14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar), alternative processing of the HGF α-chain mRNA generates anti-angiogenic HGF fragments consisting of either the first kringle domain (NK1) or the first two kringle domains (NK2) (14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar). These first two kringles contain the HGF binding site for its receptor, c-Met (14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar). NK1 and NK2 suppress HGF-induced endothelial cell migration and abrogate HGF-induced angiogenesis in the rat cornea (14.Rosen E.M. Lamszus K. Laterra J. Polverini P.J. Rubin J.S. Goldberg I.D. Gherardi E. Plasminogen-related Growth Factors. John Wiley & Sons, Chichester, United Kingdom1997: 215-226Google Scholar). These observations led to recombinant construction of NK4, which contains all four kringle domains of HGF (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). HGF/NK4 is a more potent antagonist of c-Met activation by HGF (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). HGF/NK4 potently inhibits tumor growthin vivo by increasing tumor cell apoptosis without affecting the proliferation rate of tumor cells (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). A similar pattern of tumor inhibition occurs through angiogenesis inhibition (16.Holmgren L. O'Reilly M.S. Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression..Nat. Med. 1995; 1: 149-153Crossref PubMed Scopus (1706) Google Scholar). Taken together, the anti-tumor activity of HGF/NK4 in vivo is at least partly mediated through an anti-angiogenic activity (15.Date K. Matsumoto K. Kubs K. Shimura H. Tanaka M. Nakamura T. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor..Oncogene. 1998; 17: 3045-3054Crossref PubMed Scopus (180) Google Scholar). Thus, expression of NK1 or NK2 or cryptic cleavage of HGF into NK1, NK2, or NK4 could counterbalance HGF-induced angiogenesis in vivo. Unique to platelets, PF4 binds surface heparin-like glycosaminoglycans on endothelial cells, thereby quenching the anti-thrombotic activity of antithrombin III (AT-III) and allowing a clot to form. Nearly two decades ago, PF4 was the first hemostatic protein demonstrated to be an inhibitor of angiogenesisin vivo (17.Taylor S. Folkman J. Protamine is an inhibitor of angiogenesis..Nature. 1982; 297: 307-312Crossref PubMed Scopus (521) Google Scholar, 18.Maione T.E. Gray G.S. Petro J. 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Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization..Blood. 1998; 91: 3289-3299Crossref PubMed Google Scholar). Further, a heparin-independent pathway of PF4 inhibition of endothelial cell growth exists. The endothelial cell stimulatory activity of epidermal growth factor and VEGF-A121, endothelial mitogens that lack heparin affinity, is susceptible to PF4 inhibition (20.Gengrinovitch S. Greenberg S.M. Cohen T. Gitay-Goren H. Rockwell P. Maione T.E. Levi B.-Z. Neufeld G. Platelet factor-4 inhibits the mitogenic activity of VEGF-121 and VEGF-165 using several concurrent mechanisms..J. Biol. Chem. 1995; 270: 15059-15065Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Moreover, an analogue of PF4 that lacks heparin affinity (rPF4-241) inhibits angiogenesis (21.Maione T.E. Gray G.S. Hunt A.J. Sharpe R.J. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity..Cancer Res. 1991; 51: 2077-2083PubMed Google Scholar). TSP-1 is the most abundant constituent of platelet α-granules and participates in efficient platelet aggregation (22.Jaffe E. Leung L.L.K. Nachman R.L. Levin R.L. Mosher D.F. Thrombospondin is the endogenous lectin of human platelets..Nature. 1982; 295: 246-248Crossref PubMed Scopus (106) Google Scholar, 23.Rabbi-Sabile S. Thibert V. Legrand C. Thrombospondin peptides inhibit the secretion-dependent phase of platelet aggregation..Blood Coagul. Fibrinolysis. 1996; 7: 237-240Crossref PubMed Scopus (10) Google Scholar). TSP-1 is a large (450 kDa), modular glycoprotein complexed with active transforming growth factor-β1 (TGF-β1) in α-granules and, upon release, can activate latent TGF-β1 secreted by endothelial cells (24.Schultz-Cherry S. Ribeiro S. Gentry L. Murphy-Ullrich J.E. Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system..J. Biol. Chem. 1994; 269: 26775-26782Abstract Full Text PDF PubMed Google Scholar). TSP-1 binds fibrin (25.Panetti T.S. Kudryk B.J. Mosher D.F. Interaction of recombinant procollagen and properdin modules of thrombospondin-1 with heparin and fibrinogen/fibrin..J. Biol. Chem. 1999; 274: 430-437Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), fibronectin (26.Iruela-Arispe M.L. Liska D.J. Sage E.H. Bornstein P. Differential expression of thrombospondin 1, 2, and 3 during murine development..Dev. Dyn. 1993; 197: 40-56Crossref PubMed Scopus (197) Google Scholar), plasminogen (27.Adams J.C. Thrombospondin-1..Int. J. Biochem. Cell Biol. 1997; 29: 861-865Crossref PubMed Scopus (101) Google Scholar), surface heparin-like glycosaminoglycans (26.Iruela-Arispe M.L. Liska D.J. Sage E.H. Bornstein P. 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Differential mechanisms targeting type I plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line..Blood. 1996; 87: 5061-5073Crossref PubMed Google Scholar) but is less effective in the inhibition of the endothelial cell membrane-associated plasminogen activator (uPA) activity (37.Fukao H. Ueshima S. Okada K. Matsuo O. The role of the pericellular fibrinolytic system in angiogenesis..Jpn. J. Physiol. 1997; 47: 161-171Crossref PubMed Scopus (21) Google Scholar) that is generated by endothelial sprouts (33.Collen A. Koolwijk P. Kroon M. von Hinsbergh V.W.M. Influence of fibrin structure on the formation and maintenance of capillary-like tubules by human microvascular endothelial cells..Angiogenesis. 1998; 2: 153-165Crossref PubMed Google Scholar, 34.Kroon M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. 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Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) and M.E. Koolwijk P. van Goor H. Weidle U.H. Collen A. van der Pluijm G. von Hinsbergh V.W.M. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices..Am. J. Pathol. 1999; 154: 1731-1742Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) and also N. E. by as pericellular Full Text Full Text PDF Scopus Google Scholar). generation of could occur via the mechanisms discussed and both the of endothelial repair and rate of plasmin fragments of and HGF may also be generated during Thus, domain and NK2, or NK4 may angiogenesis induced by the activity of platelet-derived angiogenic growth factors and fibrin during Platelet proteins and cryptic fragments generated during and fibrinolysis may endothelial cell during and control the rate of angiogenesis during vessel The of the hemostatic system to proteins that angiogenesis a new to angiogenesis is by and with during vessel