The Hemostatic System as a Regulator of Angiogenesis

Abstract

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. Haemostasis. 1998; 80: 171-175Crossref PubMed Scopus (239) Google Scholar), basic fibroblast growth factor (bFGF) (3.Brunner G. Nguyen H. Gabrilove J. Rifkin D.B. Wilson E.L. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells..Blood. 1993; 81: 631-638Crossref PubMed Google Scholar), hepatocyte growth factor (HGF) (4.Nakamura T. Teramoto H. Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary culture..Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 6489-6493Crossref PubMed Scopus (620) Google Scholar), angiopoietin-1, 2G. D. Yancopoulos, personal communication. insulin-like growth factor-1 and -2 (6.Karey K.P. Marquardt H. Sirbasku D.A. Human platelet-derived mitogens. I. Identification of insulin-like growth factors I and II by purification and N-terminal amino acid sequence analysis..Blood. 1989; 74: 1084-1092Crossref PubMed Google Scholar, 7.Karey K.P. Sirbasku D.A. Human platelet-derived mitogens. II. Subcellular localization of insulin-like growth factor I to the alpha granule and release in response to thrombin..Blood. 1989; 74: 1093-1100Crossref PubMed Google Scholar), epidermal growth factor (8.Ben-Ezra J. Sheibani K. Hwabg D.L. Lev-Ran A. Megakaryocyte synthesis is the source of epidermal growth factor in human platelets..Am. J. Pathol. 1990; 137: 755-759PubMed Google Scholar, 9.Hwang D.L. Lev-Ran A. Yen C.F. Sniecinski I. Release of different fractions of epidermal growth factor from human platelets in vitro: preferential release of 140 kDa fraction..Regul. Pept. 1992; 37: 95-100Crossref PubMed Scopus (17) Google Scholar), platelet-derived growth factor (10.Bar R.S. Boes M. Booth B.A. Dake B.L. Henley S. Hart M.N. The effects of platelet-derived growth factor in cultured microvessel endothelial cells..Endocrinology. 1989; 124: 1841-1848Crossref PubMed Scopus (111) Google Scholar, 11.Heldin C.-H. Westermark B. Wasteson A. Platelet-derived growth factor: isolation by a large-scale procedure and analysis of subunit composition..Biochem. J. 1981; 193: 907-913Crossref PubMed Scopus (147) Google Scholar), and sphingosine 1-phosphate (12.Lee O.-H. Kim Y.-M. Lee Y.M. Moon E.-J. Lee D.-J. Kim J.-H. Kim K.-W. Kwon Y.-G. Sphingosine 1-phosphate induces angi