Download PDF
Thromb Haemost 2013; 109(05): 940-947
DOI: 10.1160/TH12-09-0679
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Soluble CD40 ligand impairs the anti-platelet function of peripheral blood angiogenic outgrowth cells via increased production of reactive oxygen species

Lara Bou Khzam
1   Laboratory of Thrombosis and Haemostasis, Montreal Heart Institute, Québec, Canada
,
Ahmed Hachem
1   Laboratory of Thrombosis and Haemostasis, Montreal Heart Institute, Québec, Canada
,
Younes Zaid
1   Laboratory of Thrombosis and Haemostasis, Montreal Heart Institute, Québec, Canada
,
Rahma Boulahya
1   Laboratory of Thrombosis and Haemostasis, Montreal Heart Institute, Québec, Canada
,
Walid Mourad
2   Department of Medicine, Université de Montréal, Québec, Canada
,
Yahye Merhi
1   Laboratory of Thrombosis and Haemostasis, Montreal Heart Institute, Québec, Canada
2   Department of Medicine, Université de Montréal, Québec, Canada
› Author Affiliations
Further Information

Publication History

Received: 19 September 2012

Accepted after major revision: 25 January 2013

Publication Date:
22 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Adult peripheral blood angiogenic early outgrowth cells (EOCs), also known as early endothelial progenitor cells, interact with other blood and vascular cells and may regulate atherothrombosis. We have previously shown that endothelial progenitor cells inhibit platelet function and thrombus formation. The CD40L/CD40 axis is a thrombo-inflammatory mediator that affects platelet and endothelial functions. It has been shown that EOCs express CD40, whereas platelets represent the major source of its soluble ligand (sCD40L), which impairs EOC function. We aimed to test the hypothesis that the sCD40L/CD40 axis affects the anti-platelet function of EOCs. Human peripheral blood mononuclear cell-derived EOCs in culture inhibited platelet aggregation. Pre-treatment of EOCs with sCD40L reduced their in-hibitory effect on platelet aggregation in a CD40-dependent manner. EOCs viability and release of the anti-aggregating agents, prostacyclin and nitric oxide, were not affected by sCD40L. However, production of reactive oxygen species (ROS) was increased in sCD40L–treated EOCs. Blockade of ROS reversed the effects of sCD40L–treated EOCs on platelet aggregation. This study reveals that the sCD40L/CD40 axis impairs the anti-platelet properties of EOCs through increased production of ROS. These data may explain the link between elevated levels of sCD40L, impaired activity of EOCs and enhanced platelet reactivity, and consequently the occurrence of atherothrombotic disease.

Keywords

CD40 - CD40L - early outgrowth cells - platelets - reactive oxygen species
 

  • References

  • 1 Kawamoto A, Losordo DW. Endothelial progenitor cells for cardiovascular regeneration. Trends Cardiovasc Med 2008; 18: 33-37.
    CrossrefPubMedSearch in Google Scholar
  • 2 Asahara T, Murohara T, Sullivan A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967.
    CrossrefPubMedSearch in Google Scholar
  • 3 Daub K, Langer H, Seizer P. et al. Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells. FASEB J 2006; 20: 2559-2561.
    CrossrefPubMedSearch in Google Scholar
  • 4 de Boer HC, Verseyden C, Ulfman LH. et al. Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell phenotype. Arterioscler Thromb Vasc Biol 2006; 26: 1653-1659.
    CrossrefPubMedSearch in Google Scholar
  • 5 Lev EI, Estrov Z, Aboulfatova K. et al. Potential role of activated platelets in homing of human endothelial progenitor cells to subendothelial matrix. Thromb Haemost 2006; 96: 498-504.
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Massberg S, Konrad I, Schurzinger K. et al. Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 2006; 203: 1221-1233.
    CrossrefPubMedSearch in Google Scholar
  • 7 Stellos K, Langer H, Daub K. et al. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 2008; 117: 206-215.
    CrossrefPubMedSearch in Google Scholar
  • 8 Stellos K, Gnerlich S, Kraemer B. et al. Platelet interaction with progenitor cells: vascular regeneration or inquiry?. Pharmacol Rep 2008; 60: 101-108.
    PubMedSearch in Google Scholar
  • 9 Mause SF, Ritzel E, Liehn EA. et al. Platelet microparticles enhance the vasore-generative potential of angiogenic early outgrowth cells after vascular injury. Circulation 2010; 122: 495-506.
    CrossrefPubMedSearch in Google Scholar
  • 10 Abou-Saleh H, Yacoub D, Theoret JF. et al. Endothelial progenitor cells bind and inhibit platelet function and thrombus formation. Circulation 2009; 120: 2230-2239.
    CrossrefPubMedSearch in Google Scholar
  • 11 Aoki J, Serruys PW, van Beusekom H. et al. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol 2005; 45: 1574-1579.
    CrossrefPubMedSearch in Google Scholar
  • 12 Kaushal S, Amiel GE, Guleserian KJ. et al. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med 2001; 07: 1035-1040.
    CrossrefPubMedSearch in Google Scholar
  • 13 Shirota T, He H, Yasui H. et al. Human endothelial progenitor cell-seeded hybrid graft: proliferative and antithrombogenic potentials in vitro and fabrication processing. Tissue engineering 2003; 09: 127-136.
    PubMedSearch in Google Scholar
  • 14 Soehnlein O, Wantha S, Simsekyilmaz S. et al. Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Science translational medicine 2011; 03: 103-198.
    PubMedSearch in Google Scholar
  • 15 Henn V, Slupsky JR, Grafe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
    CrossrefPubMedSearch in Google Scholar
  • 16 Hristov M, Gumbel D, Lutgens E. et al. Soluble CD40 ligand impairs the function of peripheral blood angiogenic outgrowth cells and increases neointimal formation after arterial injury. Circulation 2010; 121: 315-324.
    CrossrefPubMedSearch in Google Scholar
  • 17 Hassan GS, Merhi Y, Mourad WM. CD154 and its receptors in inflammatory vascular pathologies. Trends Immunol 2009; 30: 165-172.
    CrossrefPubMedSearch in Google Scholar
  • 18 Karmann K, Hughes CC, Schechner J. et al. CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad Sci U S A 1995; 92: 4342-4346.
    CrossrefPubMedSearch in Google Scholar
  • 19 Rizvi M, Pathak D, Freedman JE. et al. CD40-CD40 ligand interactions in ox-idative stress, inflammation and vascular disease. Trends Mol Med 2008; 14: 530-538.
    CrossrefPubMedSearch in Google Scholar
  • 20 Mach F, Schonbeck U, Fabunmi RP. et al. T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L–dependent mechanism: implications for tubule formation. Am J Pathol 1999; 154: 229-238.
    CrossrefPubMedSearch in Google Scholar
  • 21 Schonbeck U, Mach F, Sukhova GK. et al. CD40 ligation induces tissue factor expression in human vascular smooth muscle cells. Am J Pathol 2000; 156: 7-14.
    CrossrefPubMedSearch in Google Scholar
  • 22 Aukrust P, Damas JK, Solum NO. Soluble CD40 ligand and platelets: self-perpetuating pathogenic loop in thrombosis and inflammation?. J Am Coll Cardiol 2004; 43: 2326-2328.
    CrossrefPubMedSearch in Google Scholar
  • 23 Urbich C, Dernbach E, Aicher A. et al. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species. Circulation 2002; 106: 981-986.
    CrossrefPubMedSearch in Google Scholar
  • 24 Chen C, Chai H, Wang X. et al. Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells. Blood 2008; 112: 3205-3216.
    CrossrefPubMedSearch in Google Scholar
  • 25 Longo CR, Arvelo MB, Patel VI. et al. A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Circulation 2003; 108: 1113-1118.
    CrossrefPubMedSearch in Google Scholar
  • 26 Chakrabarti S, Blair P, Freedman JE. CD40-40L signalling in vascular inflammation. J Biol Chem 2007; 282: 18307-18317.
    CrossrefPubMedSearch in Google Scholar
  • 27 Mead LE, Prater D, Yoder MC. et al. Isolation and characterisation of endothelial progenitor cells from human blood. Curr Protoc Stem Cell Biol. 2008 Chapter 2: Unit 2C 1
    PubMedSearch in Google Scholar
  • 28 Yamamoto K, Takahashi T, Asahara T. et al. Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress. J Appl Physiol 2003; 95: 2081-2088.
    CrossrefPubMedSearch in Google Scholar
  • 29 Hur J, Yoon CH, Kim HS. et al. Characterisation of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 2004; 24: 288-293.
    CrossrefPubMedSearch in Google Scholar
  • 30 Sieveking DP, Ng MK. Cell therapies for therapeutic angiogenesis: back to the bench. Vasc Med 2009; 14: 153-166.
    CrossrefPubMedSearch in Google Scholar
  • 31 Ingram DA, Mead LE, Tanaka H. et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004; 104: 2752-2760.
    CrossrefPubMedSearch in Google Scholar
  • 32 Prater DN, Case J, Ingram DA. et al. Working hypothesis to redefine endothelial progenitor cells. Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK; 2007. 21 pp. 1141-1149.
    Search in Google Scholar
  • 33 Pearson JD. Endothelial progenitor cells - hype or hope?. J Thromb Haemost 2009; 07: 255-262.
    CrossrefPubMedSearch in Google Scholar
  • 34 Zhang Y, Ingram DA, Murphy MP. et al. Release of proinflammatory mediators and expression of proinflammatory adhesion molecules by endothelial progenitor cells. Am J Physiol Heart Circ Physiol 2009; 296: H1675-1682.
    CrossrefPubMedSearch in Google Scholar
  • 35 Krenning G, van der Strate B, Schipper M. et al. CD34(+) Cells Augment Endothelial Cell Differentiation of CD14(+) Endothelial Progenitor Cells in vitro. J Cell Mol Med 2009; 13: 2521-2533.
    CrossrefPubMedSearch in Google Scholar
  • 36 Yoon CH, Hur J, Park KW. et al. Synergistic neovascularisation by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation 2005; 112: 1618-1627.
    CrossrefPubMedSearch in Google Scholar
  • 37 Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008; 28: 1584-1595.
    CrossrefPubMedSearch in Google Scholar
  • 38 Rehman J, Li J, Orschell CM. et al. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107: 1164-1169.
    CrossrefPubMedSearch in Google Scholar
  • 39 Co M, Tay E, Lee CH. et al. Use of endothelial progenitor cell capture stent (Genous Bio-Engineered R Stent) during primary percutaneous coronary intervention in acute myocardial infarction: intermediate- to long-term clinical follow-up. Am Heart J 2008; 155: 128-132.
    CrossrefPubMedSearch in Google Scholar
  • 40 Antoniades C, Bakogiannis C, Tousoulis D. et al. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009; 54: 669-677.
    CrossrefPubMedSearch in Google Scholar
  • 41 Lievens D, Eijgelaar WJ, Biessen EA. et al. The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost 2009; 102: 206-214.
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 de Lemos JA, Zirlik A, Schonbeck U. et al. Associations between soluble CD40 ligand, atherosclerosis risk factors, and subclinical atherosclerosis: results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol 2005; 25: 2192-2196.
    CrossrefPubMedSearch in Google Scholar
  • 43 Lievens D, Zernecke A, Seijkens T. et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116: 4317-4327.
    CrossrefPubMedSearch in Google Scholar