nach oben

Erschienen in:

01.01.2013 | Original Contribution

Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis

verfasst von: Isabella Kanzler, Nancy Tuchscheerer, Guy Steffens, Sakine Simsekyilmaz, Simone Konschalla, Andreas Kroh, David Simons, Yaw Asare, Andreas Schober, Richard Bucala, Christian Weber, Jürgen Bernhagen, Elisa A. Liehn

Erschienen in: Basic Research in Cardiology | Ausgabe 1/2013

Einloggen, um Zugang zu erhalten

Abstract

This study aimed to analyze the role of endothelial progenitor cell (EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor (MIF)/chemokine receptor axis. Primary murine and murine embryonic EPCs (eEPCs) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis, focusing on the influence of hypoxic versus normoxic stimulation. Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These factors stimulated the transmigration activity and adhesive capacity of EPCs, with MIF and VEGF exhibiting the strongest effects under hypoxia. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs enhanced tube formation, with MIF and VEGF exhibiting again the strongest effect following hypoxia. Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF. Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12, whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell (SMC) phenotype, indicating an angiogenic and differentiation capacity in vivo. Surprisingly, CXCL12, a chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. We have identified a role for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. By discerning the contributions of key angiogenic chemokines and EPCs, these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors, EPCs, and the angiogenic target tissue.

Nur mit Berechtigung zugänglich

Amin MA, Volpert OV, Woods JM, Kumar P, Harlow LA, Koch AE (2003) Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ Res 93:321–329. doi:10.1161/01.RES.0000087641.56024.DA PubMedCrossRef

Anghelina M, Krishnan P, Moldovan L, Moldovan NI (2004) Monocytes and macrophages form branched cell columns in matrigel: implications for a role in neovascularization. Stem Cells Dev 13:665–676. doi:10.1089/scd.2004.13.665 PubMedCrossRef

Anghelina M, Krishnan P, Moldovan L, Moldovan NI (2006) Monocytes/macrophages cooperate with progenitor cells during neovascularization and tissue repair: conversion of cell columns into fibrovascular bundles. Am J Pathol 168:529–541PubMedCrossRef

Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967. doi:10.1126/science.275.5302.964 PubMedCrossRef

Belo AV, Leles F, Barcelos LS, Ferreira MA, Bakhle YS, Teixeira MM, Andrade SP (2005) Murine chemokine CXCL2/KC is a surrogate marker for angiogenic activity in the inflammatory granulation tissue. Microcirculation 12:597–606. doi:10.1080/10739680500253535 PubMedCrossRef

Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596. doi:10.1038/nm1567 PubMedCrossRef

Bernhagen J, Mitchell RA, Calandra T, Voelter W, Cerami A, Bucala R (1994) Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration Inhibitory factor (MIF). Biochemistry 33:14144–14155PubMedCrossRef

Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660. doi:10.1038/nm0603-653 PubMedCrossRef

Carmeliet P (2000) VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 6:1102–1103. doi:10.1038/80430 PubMedCrossRef

10.

Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. doi:10.1038/nm1075 PubMedCrossRef

11.

Chesney J, Metz C, Bacher M, Peng T, Meinhardt A, Bucala R (1999) An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med 5:181–191 (PMCID: PMC2230298)PubMed

12.

Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, Bruno S, Bussolati B, Camussi G (2007) Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 110:2440–2448. doi:10.1182/blood-2007-03-078709 PubMedCrossRef

13.

Dewor M, Steffens G, Krohn R, Weber C, Baron J, Bernhagen J (2007) Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch-wounded monolayers in vitro. FEBS Lett 581:4734–4742. doi:10.1016/j.febslet.2007.08.071 pii: S0014-5793(07)00958-1PubMedCrossRef

14.

Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25. doi:10.1210/er.18.1.4 PubMedCrossRef

15.

Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676. doi:10.1038/nm0603-669 PubMedCrossRef

16.

Flieger O, Engling A, Bucala R, Lue H, Nickel W, Bernhagen J (2003) Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter. FEBS Lett 551:78–86 pii:S0014579303009001PubMedCrossRef

17.

Folkman J (1998) Angiogenic therapy of the human heart. Circulation 97:628–629. doi:10.1161/01.CIR.97.7.628 PubMedCrossRef

18.

Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N (1999) VEGF is required for growth and survival in neonatal mice. Development 126:1149–1159PubMed

19.

Grieb G, Piatkowski A, Simons D, Hormann N, Dewor M, Steffens G, Bernhagen J, Pallua N (2012) Macrophage migration inhibitory factor is a potential inducer of endothelial progenitor cell mobilization after flap operation. Surgery 151:268-277.e261. doi:10.1016/j.surg.2010.10.008

20.

Hatzopoulos AK, Folkman J, Vasile E, Eiselen GK, Rosenberg RD (1998) Isolation and characterization of endothelial progenitor cells from mouse embryos. Development 125:1457–1468PubMed

21.

Hinkel R, El-Aouni C, Olson T, Horstkotte J, Mayer S, Muller S, Willhauck M, Spitzweg C, Gildehaus FJ, Munzing W, Hannappel E, Bock-Marquette I, DiMaio JM, Hatzopoulos AK, Boekstegers P, Kupatt C (2008) Thymosin beta4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection. Circulation 117:2232–2240. doi:10.1161/CIRCULATIONAHA.107.758904 PubMedCrossRef

22.

Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, Oh BH, Lee MM, Park YB (2004) Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 24:288–293. doi:10.1161/01.ATV.0000114236.77009.06 PubMedCrossRef

23.

Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, Pollok K, Ferkowicz MJ, Gilley D, Yoder MC (2004) Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104:2752–2760. doi:10.1182/blood-2004-04-1396 PubMedCrossRef

24.

Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM (2004) Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 172:2853–2860PubMed

25.

Klug MG, Soonpaa MH, Koh GY, Field LJ (1996) Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Investig 98:216–224. doi:10.1172/JCI118769 PubMedCrossRef

26.

Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S (2005) Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 105:3793–3801. doi:10.1182/blood-2004-11-4349 PubMedCrossRef

27.

Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (2005) Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 23:879–894. doi:10.1634/stemcells.2004-0342 PubMedCrossRef

28.

Kupatt C, Bock-Marquette I, Boekstegers P (2008) Embryonic endothelial progenitor cell-mediated cardioprotection requires Thymosin beta4. Trends Cardiovasc Med 18:205–210. doi:10.1016/j.tcm.2008.10.002 PubMedCrossRef

29.

Kupatt C, Horstkotte J, Vlastos GA, Pfosser A, Lebherz C, Semisch M, Thalgott M, Buttner K, Browarzyk C, Mages J, Hoffmann R, Deten A, Lamparter M, Muller F, Beck H, Buning H, Boekstegers P, Hatzopoulos AK (2005) Embryonic endothelial progenitor cells expressing a broad range of proangiogenic and remodeling factors enhance vascularization and tissue recovery in acute and chronic ischemia. FASEB J 19:1576–1578. doi:10.1096/fj.04-3282fje PubMed

30.

Lassaletta AD, Chu LM, Sellke FW (2011) Therapeutic neovascularization for coronary disease: current state and future prospects. Basic Res Cardiol 106:897–909. doi:10.1007/s00395-011-0200-1 PubMedCrossRef

31.

Liehn EA, Postea O, Curaj A, Marx N (2011) Repair after myocardial infarction, between fantasy and reality: the role of chemokines. J Am Coll Cardiol 58:2357–2362. http://dx.doi.org/10.1016/j.jacc.2011.08.034

32.

Liehn EA, Schober A, Weber C (2004) Blockade of keratinocyte-derived chemokine inhibits endothelial recovery and enhances plaque formation after arterial injury in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 24:1891–1896. doi:10.1161/01.ATV.0000143135.71440.75 PubMedCrossRef

33.

Liehn EA, Tuchscheerer N, Kanzler I, Drechsler M, Fraemohs L, Schuh A, Koenen RR, Zander S, Soehnlein O, Hristov M, Grigorescu G, Urs AO, Leabu M, Bucur I, Merx MW, Zernecke A, Ehling J, Gremse F, Lammers T, Kiessling F, Bernhagen J, Schober A, Weber C (2011) Double-edged role of the CXCL12/CXCR4 axis in experimental myocardial infarction. J Am Coll Cardiol 58:2415-2423. http://dx.doi.org/10.1016/j.jacc.2011.08.033

34.

Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J (2002) Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 4:449–460 pii:S1286457902015605PubMedCrossRef

35.

Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 95:9448–9453 (PMCID: PMC21358Immunology)PubMedCrossRef

36.

Mammoto A, Connor KM, Mammoto T, Yung CW, Huh D, Aderman CM, Mostoslavsky G, Smith LE, Ingber DE (2009) A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457:1103–1108. doi:10.1038/nature07765 PubMedCrossRef

37.

Poss J, Werner C, Lorenz D, Gensch C, Bohm M, Laufs U (2010) The renin inhibitor aliskiren upregulates pro-angiogenic cells and reduces atherogenesis in mice. Basic Res Cardiol 105:725–735. doi:10.1007/s00395-010-0120-5 PubMedCrossRef

38.

Rehman J, Li J, Orschell CM, March KL (2003) Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169. doi:10.1161/01.CIR.0000058702.69484.A0 PubMedCrossRef

39.

Schober A, Bernhagen J, Thiele M, Zeiffer U, Knarren S, Roller M, Bucala R, Weber C (2004) Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice. Circulation 109:380–385. doi:10.1161/01.CIR.0000109201.72441.09 PubMedCrossRef

40.

Schober A, Knarren S, Lietz M, Lin EA, Weber C (2003) Crucial role of stromal cell-derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice. Circulation 108:2491–2497. doi:10.1161/01.CIR.0000099508.76665.9A PubMedCrossRef

41.

Schuh A, Liehn EA, Sasse A, Hristov M, Sobota R, Kelm M, Merx MW, Weber C (2008) Transplantation of endothelial progenitor cells improves neovascularization and left ventricular function after myocardial infarction in a rat model. Basic Res Cardiol 103:69–77. doi:10.1007/s00395-007-0685-9 PubMedCrossRef

42.

Simons D, Grieb G, Hristov M, Pallua N, Weber C, Bernhagen J, Steffens G (2011) Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med 15:668–678. doi:10.1111/j.1582-4934-2010-01-041.x PubMedCrossRef

43.

Simons M, Bonow RO, Chronos NA, Cohen DJ, Giordano FJ, Hammond HK, Laham RJ, Li W, Pike M, Sellke FW, Stegmann TJ, Udelson JE, Rosengart TK (2000) Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 102:E73–E86. doi:10.1161/01.CIR.102.11.e73 PubMedCrossRef

44.

Vajkoczy P, Blum S, Lamparter M, Mailhammer R, Erber R, Engelhardt B, Vestweber D, Hatzopoulos AK (2003) Multistep nature of microvascular recruitment of ex vivo-expanded embryonic endothelial progenitor cells during tumor angiogenesis. J Exp Med 197:1755–1765. doi:10.1084/jem.20021659 PubMedCrossRef

45.

Walcher D, Vasic D, Heinz P, Bach H, Durst R, Hausauer A, Hombach V, Marx N (2010) LXR activation inhibits chemokine-induced CD4-positive lymphocyte migration. Basic Res Cardiol 105:487–494. doi:10.1007/s00395-010-0092-5 PubMedCrossRef

46.

Walenta KL, Bettink S, Bohm M, Friedrich EB (2011) Differential chemokine receptor expression regulates functional specialization of endothelial progenitor cell subpopulations. Basic Res Cardiol 106:299–305. doi:10.1007/s00395-010-0142-z PubMedCrossRef

47.

Zernecke A, Bernhagen J, Weber C (2008) Macrophage migration inhibitory factor in cardiovascular disease. Circulation 117:1594–1602. doi:10.1161/CIRCULATIONAHA.107.729125 PubMedCrossRef

Titel: Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis
verfasst von: Isabella Kanzler
Nancy Tuchscheerer
Guy Steffens
Sakine Simsekyilmaz
Simone Konschalla
Andreas Kroh
David Simons
Yaw Asare
Andreas Schober
Richard Bucala
Christian Weber
Jürgen Bernhagen
Elisa A. Liehn
Publikationsdatum: 01.01.2013
Verlag: Springer-Verlag
Erschienen in: Basic Research in Cardiology / Ausgabe 1/2013
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0310-4

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Differential roles of angiogenic chemokines in endothelial progenitor cell-induced angiogenesis

Abstract

Neu im Fachgebiet Kardiologie

Ist Fasten vor Koronarinterventionen wirklich nötig?

PET kann infarktgefährdete Koronararterien entdecken

GLP-1-Agonist Semaglutid wirkt kardio- und nephroprotektiv

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

Update Kardiologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2013

Remote ischemic preconditioning regulates HIF-1α levels, apoptosis and inflammation in heart tissue of cardiosurgical patients: a pilot experimental study

Cardiac primitive cells become committed to a cardiac fate in adult human heart with chronic ischemic disease but fail to acquire mature phenotype: genetic and phenotypic study

Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques

Activation of Liver X receptors in the heart leads to accumulation of intracellular lipids and attenuation of ischemia–reperfusion injury

Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload

Cardiac-derived adiponectin induced by long-term insulin treatment ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic mice via AMPK signaling

Neu im Fachgebiet Kardiologie

Ist Fasten vor Koronarinterventionen wirklich nötig?

PET kann infarktgefährdete Koronararterien entdecken

GLP-1-Agonist Semaglutid wirkt kardio- und nephroprotektiv

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

Update Kardiologie