Abstract
Atherosclerosis involves angiogenesis and inflammation with the ability of endothelial cells and monocytes to respond to chemokines. We addressed here by in vitro and in vivo approaches, the role of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)/CCL5 on angiogenesis through its receptors CCR1, CCR5, syndecan-1 (SDC-1), syndecan-4 (SDC-4) and CD-44. Our data demonstrate that RANTES/CCL5 is pro-angiogenic in a rat subcutaneous model. This RANTES/CCL5-activity may be related to the in vitro promotion of endothelial cell migration, spreading and neo-vessel formation. RANTES/CCL5-mediated angiogenesis depends at least partly on Vascular Endothelial Growth Factor (VEGF) secretion by endothelial cells, since this effect is decreased when endothelial cells are incubated with anti-VEGF receptor antibodies. RANTES/CCL5-induced chemotaxis is mediated by matrix metalloproteinase-9. We demonstrate that specific receptors of RANTES/CCL5 such as G protein-coupled receptors CCR1 and CCR5, and heparan sulfate proteoglycans, SDC-1, SDC-4 or CD-44, play a major role in RANTES/CCL5-induced angiogenic effects. By the use of two RANTES/CCL5 mutants, [E66A]-RANTES/CCL5 with impaired ability to oligomerize, and [44AANA47]-RANTES/CCL5 mutated in the main RANTES/CCL5-glycosaminoglycan (GAG) binding site, we demonstrate that chemokine oligomerization and binding to GAGs are essential in RANTES/CCL5-induced angiogenic effects. According to these results, new therapeutic strategies based on RANTES/CCL5 can be proposed for neo-angiogenesis after vascular injury. Mutants of RANTES/CCL5 may also represent an innovative approach to prevent the angiogenesis associated with the formation of atherosclerotic plaque.
Similar content being viewed by others
References
Braunersreuther V, Mach F, Steffens S (2007) The specific role of chemokines in atherosclerosis. Thromb Haemost 97:714–721
Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86:515–581
Van Hinsbergh V, Koolwijk P (2008) Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 78:203–221
Salcedo R, Oppenheim JJ (2003) Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 10:359–370
Khurana R, Simons M, Martin JF, Zachary IC (2005) Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation 112:1813–1824
Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621
Baltus T, von Hundelshausen P, Mause SF, Buhre W, Rossaint R, Weber C (2005) Differential and additive effects of platelet-derived chemokines on monocyte arrest on inflamed endothelium under flow conditions. J Leukoc Biol 78:435–441
Hayes IM, Jordan NJ, Towers S et al (1998) Human vascular smooth muscle cells express receptors for CC chemokines. Arterioscler Thromb Vasc Biol 18:397–403
Pattison JM, Nelson PJ, Huie P, Sibley RK, Krensky AM (1996) RANTES chemokine expression in transplant-associated accelerated atherosclerosis. J Heart Lung Transplant 15:1194–1199
Von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C (2001) RANTES RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 103:1772–1777
Proudfoot AE, Handel TM, Johnson Z et al (2003) Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc Natl Acad Sci USA 100:1885–1890
Braunersreuther V, Pellieux C, Pelli G et al (2010) Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice. J Mol Cell Cardiol 48:789–798
Segerer S, Johnson Z, Rek A et al (2009) The basic residue cluster (55)KKWVR(59) in CCL5 is required for in vivo biologic function. Mol Immunol 46:2533–2538
Solari R, Offord RE, Remy S et al (1997) Receptor-mediated endocytosis of CC-chemokines. J Biol Chem 272:9617–9620
Baltus T, Weber KS, Johnson Z, Proudfoot AE, Weber C (2003) Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium. Blood 102:1985–1988
Johnson Z, Kosco-Vilbois MH, Herren S et al (2004) Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J Immunol 173:5776–5785
Parissis JT, Adamopoulos S, Venetsanou KF, Mentzikof DG, Karas SM, Kremastinos DT (2002) Serum profiles of CC chemokines in acute myocardial infarction: possible implication in postinfarction left ventricular remodeling. J Interferon Cytokine Res 22:223–229
Veillard NR, Kwak B, Pelli G, Mulhaupt F, James RW, Proudfoot AE, Mach F (2004) Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ Res 94:253–261
Barcelos LS, Coelho AM, Russo RC et al (2009) Role of the chemokines CCL3/MIP-1 alpha and CCL5/RANTES in disc-induced inflammatory angiogenesis in mice. Microvasc Res 78:148–154
Bernardini G, Ribatti D, Spinetti G et al (2003) Analysis of the role of chemokines in angiogenesis. J Immunol Methods 273:83–101
Charni F, Friand V, Haddad O et al (2009) Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells. Biochim Biophys Acta 1790:1314–1326
Vita C, Drakopoulou E, Ylisastigui L et al (2002) Synthesis and characterization of biologically functional biotinylated RANTES. J Immunol Methods 266:53–65
Korff T, Augustin HG (1998) Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol 143:1341–1352
Davis GE, Camarillo CW (1996) An alpha 2 beta 1 integrin-dependent pinocytic mechanism involving intracellular vacuole formation and coalescence regulates capillary lumen and tube formation in three-dimensional collagen matrix. Exp Cell Res 224:39–51
Bayless KJ, Davis GE (2003) Sphingosine-1-phosphate markedly induces matrix metalloproteinase and integrin-dependent human endothelial cell invasion and lumen formation in three-dimensional collagen and fibrin matrices. Biochem Biophys Res Commun 12:903–913
Sutton A, Friand V, Brule-Donneger S et al (2007) Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res 5:21–33
Hlawaty H, Suffee N, Sutton A et al (2011) Low molecular weight fucoidan prevents intimal hyperplasia in rat injured thoracic aorta through the modulation of matrix metalloproteinase-2 expression. Biochem Pharmacol 81:233–243
Feldman LJ, Mazighi M, Scheuble A et al (2001) Differential expression of matrix metalloproteinases after stent implantation and balloon angioplasty in the hypercholesterolemic rabbit. Circulation 103(25):3117–3122
Park BH, Song KJ, Yoon SJ et al (2011) Acceleration of spinal fusion using COMP-angiopoietin 1 with allografting in a rat model. Bone 49:447–454
Elcin AE, Elcin YM (2006) Localized angiogenesis induced by human vascular endothelial growth factor-activated PLGA disc. Tissue Eng 12:959–968
Willard M, Liang K, Yoon Y, Kang S, Shim H (2007) CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun 359:716–722
Varney ML, Olsen KJ, Mosley RL, Singh RK (2005) Paracrine regulation of vascular endothelial growth factor-a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. J Interferon Cytokine Res 11:674–683
Jain RK, Finn AV, Kolodgie FD et al (2007) Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat Clin Pract Cardiovasc Med 4:491–502
Von Luettichau I, Nelson PJ, Pattison JM et al (1996) RANTES chemokine expression in diseased and normal human tissues. Cytokine 8:89–98
Azenshtein E, Luboshits G, Shina S (2002) The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity. Cancer Res 62:1093–1102
Suffee N, Richard B, Hlawaty H, Oudar O, Charnaux N (2011) Angiogenic properties of the chemokine RANTES/CCL5. Biochem Soc Trans 39:1649–1653
Westerweel PE, Rabelink TJ, Rookmaaker MB, Gröne HJ, Verhaar MC (2008) RANTES is required for ischaemia-induced angiogenesis, which may hamper RANTES-targeted anti-atherosclerotic therapy. Thromb Haemost 99:794–795
Ambati BK, Anand A, Joussen AM, Kuziel WA, Adamis AP, Ambati J (2003) Sustained inhibition of corneal neovascularization by genetic ablation of CCR5. Invest Ophthalmol Vis Sci 44:590–593
Cochain C, Rodero MP, Vilar J (2010) Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization. Cardiovasc Res 88:186–195
Zernecke A, Shagdarsuren E, Weber C (2008) Chemokines in atherosclerosis: an update. Arterioscler Thromb Vasc Biol 28:1897–1908
Son KN, Hwang J, Kwon BS, Kim J (2006) Human CC chemokine CCL23 enhances expression of matrix metalloproteinase-2 and invasion of vascular endothelial cells. Biochem Biophys Res Commun 340:498–504
Brule S, Charnaux N, Sutton A, Ledoux D, Chaigneau T, Saffar L, Gattegno L (2006) The shedding of syndecan-4 and syndecan-1 from HeLa cells and human primary macrophages is accelerated by SDF-1/CXCL12 and mediated by the matrix metalloproteinase-9. Glycobiology 16:488–501
Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S (2004) CXC chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol 25:201–209
Von Hundelshausen P, Petersen F, Brandt E (2007) Platelet-derived chemokines in vascular biology. Thromb Haemost 97:704–713
Rookmaaker MB, Verhaar MC, de Boer HC et al (2007) Met-RANTES reduces endothelial progenitor cell homing to activated (glomerular) endothelium in vitro and in vivo. Am J Physiol Renal Physiol 293:624–630
Charnaux N, Brule S, Chaigneau T et al (2005) RANTES (CCL5) induces a CCR5-dependent accelerated shedding of syndecan-1 (CD138) and syndecan-4 from HeLa cells and forms complexes with the shed ectodomains of these proteoglycans as well as with those of CD44. Glycobiology 15:119–130
Slimani H, Charnaux N, Mbemba E, Saffar L, Vassy R, Vita C, Gattegno L (2003) Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages. Biochim Biophys Acta 1617:80–88
Martin L, Blanpain C, Garnier P, Wittamer V, Parmentier M, Vita C (2001) Structural and functional analysis of the RANTES-glycosaminoglycans interactions. Biochemistry 40:6303–6318
Proudfoot AE, Fritchley S, Borlat F et al (2001) The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J Biol Chem 276:10620–10626
Acknowledgments
This work was supported by the Direction de la Recherche et des Enseignements Doctoraux (Ministère de l’Enseignement Supérieur et de la Recherche), the University Paris 13 and INSERM. N. Suffee was supported by a fellowship from Ministère de l’Enseignement Supérieur et de la Recherche (France).
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Suffee, N., Hlawaty, H., Meddahi-Pelle, A. et al. RANTES/CCL5-induced pro-angiogenic effects depend on CCR1, CCR5 and glycosaminoglycans. Angiogenesis 15, 727–744 (2012). https://doi.org/10.1007/s10456-012-9285-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-012-9285-x