Interaction of endothelial cells with macrophages—linking molecular and metabolic signaling

Invited Review


Angiogenesis and inflammation go hand in hand in various (patho-)physiological conditions. Several studies have highlighted the interconnection between endothelial cells (ECs) and macrophages in these conditions at the level of growth factor and cytokine signaling, yet the importance of metabolism and metabolic signaling has been largely overlooked. Modulating macrophage and/or endothelial functions by interfering with metabolic pathways offers new perspectives for therapeutic strategies. In this review, we highlight the complexity of the interrelationship between the inflammatory response and angiogenesis. More in particular, the interaction between macrophages and ECs will be discussed with a special focus on how their metabolism can contribute to (patho-)physiological conditions.


Macrophages Endothelial cells Angiogenesis Inflammation Cell metabolism 



J.K. is supported by Research Foundation Flanders (FWO) Postdoctoral Fellowships, B.W. is a Heisenberg Professor and has been supported by grants from the DFG (WI 3291/1-1, 1-2, 3, and 5), and L.B. is funded by a grant of the Leopoldina German National Academy of Sciences. P.C. is supported by Federal Government Belgium grant (IUAP P7/03), long-term structural Methusalem funding by the Flemish Government, the Research Foundation Flanders (FWO), the Foundation Leducq Transatlantic Network (ARTEMIS), Foundation Against Cancer, a European Research Council (ERC) Advanced Research Grant (EU-ERC269073), and the AXA Research Fund. GE is supported by FWO (KAN2014


  1. 1.
    Alkim C, Alkim H, Koksal AR, Boga S, Sen I (2015) Angiogenesis in inflammatory bowel disease. Int J Inflam 2015:970890. doi: 10.1155/2015/970890 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Alphonsus CS, Rodseth RN (2014) The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia 69:777–784. doi: 10.1111/anae.12661 CrossRefPubMedGoogle Scholar
  3. 3.
    Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. doi: 10.1146/annurev.immunol.021908.132557 CrossRefPubMedGoogle Scholar
  4. 4.
    Back M, Weber C, Lutgens E (2015) Regulation of atherosclerotic plaque inflammation. J Intern Med 278:462–482. doi: 10.1111/joim.12367 CrossRefPubMedGoogle Scholar
  5. 5.
    Baer C, Squadrito ML, Iruela-Arispe ML, De Palma M (2013) Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches. Exp Cell Res 319:1626–1634. doi: 10.1016/j.yexcr.2013.03.026 CrossRefPubMedGoogle Scholar
  6. 6.
    Biswas SK, Mantovani A (2012) Orchestration of metabolism by macrophages. Cell Metab 15:432–437. doi: 10.1016/j.cmet.2011.11.013 CrossRefPubMedGoogle Scholar
  7. 7.
    Bobryshev YV, Ivanova EA, Chistiakov DA, Nikiforov NG, Orekhov AN (2016) Macrophages and their role in atherosclerosis: pathophysiology and transcriptome analysis. Biomed Res Int 2016:9582430. doi: 10.1155/2016/9582430 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Boueiz A, Hassoun PM (2009) Regulation of endothelial barrier function by reactive oxygen and nitrogen species. Microvasc Res 77:26–34. doi: 10.1016/j.mvr.2008.10.005 CrossRefPubMedGoogle Scholar
  9. 9.
    Bruce AC, Kelly-Goss MR, Heuslein JL, Meisner JK, Price RJ, Peirce SM (2014) Monocytes are recruited from venules during arteriogenesis in the murine spinotrapezius ligation model. Arterioscler Thromb Vasc Biol 34:2012–2022. doi: 10.1161/ATVBAHA.114.303399 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquiere B, Rehman J, Lambrechts D, Malik AB, Dewerchin M, Carmeliet P (2016) Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30:968–985. doi: 10.1016/j.ccell.2016.10.006 CrossRefPubMedGoogle Scholar
  11. 11.
    Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307. doi: 10.1038/nature10144 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24:695–709. doi: 10.1016/j.ccr.2013.11.007 CrossRefPubMedGoogle Scholar
  13. 13.
    Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Kundu RK, Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird WC, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T (2008) Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322:1101–1104. doi: 10.1126/science.1165218 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563. doi: 10.1038/nature13490 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T (1995) Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 9:899–909PubMedGoogle Scholar
  16. 16.
    Cook-Mills JM, Marchese ME, Abdala-Valencia H (2011) Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants. Antioxid Redox Signal 15:1607–1638. doi: 10.1089/ars.2010.3522 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS (2011) Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol 17:578–593. doi: 10.3748/wjg.v17.i5.578 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    De Bock K, Georgiadou M, Carmeliet P (2013a) Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18:634–647. doi: 10.1016/j.cmet.2013.08.001 CrossRefPubMedGoogle Scholar
  19. 19.
    De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiere B, Cauwenberghs S, Eelen G, Phng LK, Betz I, Tembuyser B, Brepoels K, Welti J, Geudens I, Segura I, Cruys B, Bifari F, Decimo I, Blanco R, Wyns S, Vangindertael J, Rocha S, Collins RT, Munck S, Daelemans D, Imamura H, Devlieger R, Rider M, Van Veldhoven PP, Schuit F, Bartrons R, Hofkens J, Fraisl P, Telang S, Deberardinis RJ, Schoonjans L, Vinckier S, Chesney J, Gerhardt H, Dewerchin M, Carmeliet P (2013b) Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154:651–663. doi: 10.1016/j.cell.2013.06.037 CrossRefPubMedGoogle Scholar
  20. 20.
    De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE (2007) Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28:519–524. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  21. 21.
    Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K, Dorn C, Hellerbrand C, Kastenberger M, Kunz-Schughart LA, Oefner PJ, Andreesen R, Gottfried E, Kreutz MP (2010) Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol 184:1200–1209. doi: 10.4049/jimmunol.0902584 CrossRefPubMedGoogle Scholar
  22. 22.
    Dixit N, Simon SI (2012) Chemokines, selectins and intracellular calcium flux: temporal and spatial cues for leukocyte arrest. Front Immunol 3:188. doi: 10.3389/fimmu.2012.00188 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Mockel D, Baeck C, Hittatiya K, Eulberg D, Luedde T, Kiessling F, Trautwein C, Lammers T, Tacke F (2014) CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63:1960–1971. doi: 10.1136/gutjnl-2013-306294 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J, Cataltepe S (2009) Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J 23:3865–3873. doi: 10.1096/fj.09-134882 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fajardo LF, Kwan HH, Kowalski J, Prionas SD, Allison AC (1992) Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol 140:539–544PubMedPubMedCentralGoogle Scholar
  26. 26.
    Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson SW, Ruhrberg C (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116:829–840. doi: 10.1182/blood-2009-12-257832 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, Pamer EG, Li MO (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921–925. doi: 10.1126/science.1252510 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P (1987) Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci U S A 84:5277–5281CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ghesquiere B, Wong BW, Kuchnio A, Carmeliet P (2014) Metabolism of stromal and immune cells in health and disease. Nature 511:167–176. doi: 10.1038/nature13312 CrossRefPubMedGoogle Scholar
  30. 30.
    Giles TD, Sander GE, Nossaman BD, Kadowitz PJ (2012) Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (Greenwich) 14:198–205. doi: 10.1111/j.1751-7176.2012.00606.x CrossRefGoogle Scholar
  31. 31.
    Gimbrone MA Jr, Garcia-Cardena G (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 118:620–636. doi: 10.1161/CIRCRESAHA.115.306301 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Giraudo E, Primo L, Audero E, Gerber HP, Koolwijk P, Soker S, Klagsbrun M, Ferrara N, Bussolino F (1998) Tumor necrosis factor-alpha regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells. J Biol Chem 273:22128–22135CrossRefPubMedGoogle Scholar
  33. 33.
    Grundmann S, Schirmer SH, Hekking LH, Post JA, Ionita MG, de Groot D, van Royen N, van den Berg B, Vink H, Moser M, Bode C, de Kleijn D, Pasterkamp G, Piek JJ, Hoefer IE (2009) Endothelial glycocalyx dimensions are reduced in growing collateral arteries and modulate leucocyte adhesion in arteriogenesis. J Cell Mol Med 13:3463–3474. doi: 10.1111/j.1582-4934.2009.00735.x CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    He H, Xu J, Warren CM, Duan D, Li X, Wu L, Iruela-Arispe ML (2012) Endothelial cells provide an instructive niche for the differentiation and functional polarization of M2-like macrophages. Blood 120:3152–3162. doi: 10.1182/blood-2012-04-422758 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hordijk PL (2016) Recent insights into endothelial control of leukocyte extravasation. Cell Mol Life Sci 73:1591–1608. doi: 10.1007/s00018-016-2136-y CrossRefPubMedGoogle Scholar
  36. 36.
    Hu Y, Kiely JM, Szente BE, Rosenzweig A, Gimbrone MA Jr (2000) E-selectin-dependent signaling via the mitogen-activated protein kinase pathway in vascular endothelial cells. J Immunol 165:2142–2148CrossRefPubMedGoogle Scholar
  37. 37.
    Huang AJ, Manning JE, Bandak TM, Ratau MC, Hanser KR, Silverstein SC (1993) Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells. J Cell Biol 120:1371–1380CrossRefPubMedGoogle Scholar
  38. 38.
    Kanczkowski W, Chatzigeorgiou A, Grossklaus S, Sprott D, Bornstein SR, Chavakis T (2013) Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction. Endocrinology 154:1181–1189. doi: 10.1210/en.2012-1617 CrossRefPubMedGoogle Scholar
  39. 39.
    Kawashima S (2004) Malfunction of vascular control in lifestyle-related diseases: endothelial nitric oxide (NO) synthase/NO system in atherosclerosis. J Pharmacol Sci 96:411–419CrossRefPubMedGoogle Scholar
  40. 40.
    Kliche K, Jeggle P, Pavenstadt H, Oberleithner H (2011) Role of cellular mechanics in the function and life span of vascular endothelium. Pflugers Arch 462:209–217. doi: 10.1007/s00424-011-0929-2 CrossRefPubMedGoogle Scholar
  41. 41.
    Koch AE, Cho M, Burrows JC, Polverini PJ, Leibovich SJ (1992) Inhibition of production of monocyte/macrophage-derived angiogenic activity by oxygen free-radical scavengers. Cell Biol Int Rep 16:415–425CrossRefPubMedGoogle Scholar
  42. 42.
    Kuwano T, Nakao S, Yamamoto H, Tsuneyoshi M, Yamamoto T, Kuwano M, Ono M (2004) Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB J 18:300–310. doi: 10.1096/fj.03-0473com CrossRefPubMedGoogle Scholar
  43. 43.
    Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201–1209. doi: 10.1172/JCI14172 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lau EK, Paavola CD, Johnson Z, Gaudry JP, Geretti E, Borlat F, Kungl AJ, Proudfoot AE, Handel TM (2004) Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1: implications for structure and function in vivo. J Biol Chem 279:22294–22305. doi: 10.1074/jbc.M311224200 CrossRefPubMedGoogle Scholar
  45. 45.
    Leveque M, Le Trionnaire S, Del Porto P, Martin-Chouly C (2016) The impact of impaired macrophage functions in cystic fibrosis disease progression. J Cyst Fibros. doi: 10.1016/j.jcf.2016.10.011 PubMedGoogle Scholar
  46. 46.
    Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7:678–689. doi: 10.1038/nri2156 CrossRefPubMedGoogle Scholar
  47. 47.
    Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, Roers A, Eming SA (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 184:3964–3977. doi: 10.4049/jimmunol.0903356 CrossRefPubMedGoogle Scholar
  48. 48.
    Mamlouk S, Kalucka J, Singh RP, Franke K, Muschter A, Langer A, Jakob C, Gassmann M, Baretton GB, Wielockx B (2014) Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development. Int J Cancer 134:849–858. doi: 10.1002/ijc.28409 CrossRefPubMedGoogle Scholar
  49. 49.
    Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13. doi: 10.12703/P6-13 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C, Auer M, Hub E, Rot A (1997) Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91:385–395CrossRefPubMedGoogle Scholar
  51. 51.
    Middleton J, Patterson AM, Gardner L, Schmutz C, Ashton BA (2002) Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100:3853–3860. doi: 10.1182/blood.V100.12.3853 CrossRefPubMedGoogle Scholar
  52. 52.
    Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Dabritz JH, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O’Neill LA (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167:457–470 e413. doi: 10.1016/j.cell.2016.08.064
  53. 53.
    Montrucchio G, Lupia E, Battaglia E, Passerini G, Bussolino F, Emanuelli G, Camussi G (1994) Tumor necrosis factor alpha-induced angiogenesis depends on in situ platelet-activating factor biosynthesis. J Exp Med 180:377–382CrossRefPubMedGoogle Scholar
  54. 54.
    Muller WA (2013) Getting leukocytes to the site of inflammation. Vet Pathol 50:7–22. doi: 10.1177/0300985812469883 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631. doi: 10.1038/nrc2444 CrossRefPubMedGoogle Scholar
  56. 56.
    Nakao S, Kuwano T, Tsutsumi-Miyahara C, Ueda S, Kimura YN, Hamano S, Sonoda KH, Saijo Y, Nukiwa T, Strieter RM, Ishibashi T, Kuwano M, Ono M (2005) Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth. J Clin Invest 115:2979–2991. doi: 10.1172/JCI23298 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nakao S, Hata Y, Miura M, Noda K, Kimura YN, Kawahara S, Kita T, Hisatomi T, Nakazawa T, Jin Y, Dana MR, Kuwano M, Ono M, Ishibashi T, Hafezi-Moghadam A (2007) Dexamethasone inhibits interleukin-1beta-induced corneal neovascularization: role of nuclear factor-kappaB-activated stromal cells in inflammatory angiogenesis. Am J Pathol 171:1058–1065. doi: 10.2353/ajpath.2007.070172 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918CrossRefPubMedGoogle Scholar
  59. 59.
    Nelson RH (2013) Hyperlipidemia as a risk factor for cardiovascular disease. Prim Care 40:195–211. doi: 10.1016/j.pop.2012.11.003 CrossRefPubMedGoogle Scholar
  60. 60.
    Omanwar S, Fahim M (2015) Mercury exposure and endothelial dysfunction: an interplay between nitric oxide and oxidative stress. Int J Toxicol 34:300–307. doi: 10.1177/1091581815589766 CrossRefPubMedGoogle Scholar
  61. 61.
    O’Neill LA, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16:553–565. doi: 10.1038/nri.2016.70 CrossRefPubMedGoogle Scholar
  62. 62.
    Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z, Avanzato D, Maione F, Hernandez-Fernaud JR, Mackay G, Zheng L, Reid S, Frezza C, Giraudo E, Fiorio Pla A, Anderson K, Ruppin E, Gottlieb E, Zanivan S (2015) Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability. Mol Cell Proteomics 14:621–634. doi: 10.1074/mcp.M114.045575 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Patterson C, Perrella MA, Endege WO, Yoshizumi M, Lee ME, Haber E (1996) Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-alpha in cultured human vascular endothelial cells. J Clin Invest 98:490–496. doi: 10.1172/JCI118816 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Pfau S, Leitenberg D, Rinder H, Smith BR, Pardi R, Bender JR (1995) Lymphocyte adhesion-dependent calcium signaling in human endothelial cells. J Cell Biol 128:969–978CrossRefPubMedGoogle Scholar
  65. 65.
    Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7:803–815. doi: 10.1038/nri2171 CrossRefPubMedGoogle Scholar
  66. 66.
    Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887. doi: 10.1016/j.cell.2011.08.039 CrossRefPubMedGoogle Scholar
  67. 67.
    Pousa ID, Mate J, Gisbert JP (2008) Angiogenesis in inflammatory bowel disease. Eur J Clin Investig 38:73–81. doi: 10.1111/j.1365-2362.2007.01914.x CrossRefGoogle Scholar
  68. 68.
    Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. doi: 10.1016/j.cell.2010.03.014 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG (2007) The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454:345–359. doi: 10.1007/s00424-007-0212-8 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 5:75. doi: 10.3389/fphys.2014.00075 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Roszer T (2015) Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat Inflamm 2015:816460. doi: 10.1155/2015/816460 CrossRefGoogle Scholar
  72. 72.
    Ruan GX, Kazlauskas A (2013) Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. J Biol Chem 288:21161–21172. doi: 10.1074/jbc.M113.474619 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Sainson RC, Johnston DA, Chu HC, Holderfield MT, Nakatsu MN, Crampton SP, Davis J, Conn E, Hughes CC (2008) TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype. Blood 111:4997–5007. doi: 10.1182/blood-2007-08-108597 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Sato N, Goto T, Haranaka K, Satomi N, Nariuchi H, Mano-Hirano Y, Sawasaki Y (1986) Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Natl Cancer Inst 76:1113–1121PubMedGoogle Scholar
  75. 75.
    Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquiere B, Cauwenberghs S, Kuchnio A, Wong BW, Quaegebeur A, Goveia J, Bifari F, Wang X, Blanco R, Tembuyser B, Cornelissen I, Bouche A, Vinckier S, Diaz-Moralli S, Gerhardt H, Telang S, Cascante M, Chesney J, Dewerchin M, Carmeliet P (2014) Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab 19:37–48. doi: 10.1016/j.cmet.2013.11.008 CrossRefPubMedGoogle Scholar
  76. 76.
    Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, Heggermont W, Godde L, Vinckier S, Van Veldhoven PP, Eelen G, Schoonjans L, Gerhardt H, Dewerchin M, Baes M, De Bock K, Ghesquiere B, Lunt SY, Fendt SM, Carmeliet P (2015) Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520:192–197. doi: 10.1038/nature14362 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Schweigerer L, Malerstein B, Gospodarowicz D (1987) Tumor necrosis factor inhibits the proliferation of cultured capillary endothelial cells. Biochem Biophys Res Commun 143:997–1004CrossRefPubMedGoogle Scholar
  78. 78.
    Sene A, Khan AA, Cox D, Nakamura RE, Santeford A, Kim BM, Sidhu R, Onken MD, Harbour JW, Hagbi-Levi S, Chowers I, Edwards PA, Baldan A, Parks JS, Ory DS, Apte RS (2013) Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab 17:549–561. doi: 10.1016/j.cmet.2013.03.009 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Shibuya M (2003) Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E. Cancer Sci 94:751–756CrossRefPubMedGoogle Scholar
  80. 80.
    Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, Piacibello W, Kumanogoh A, Kikutani H, Comoglio PM, Tamagnone L, Giordano S (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685. doi: 10.1084/jem.20072602 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Sun J, Paddock C, Shubert J, Zhang HB, Amin K, Newman PJ, Albelda SM (2000) Contributions of the extracellular and cytoplasmic domains of platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) in regulating cell-cell localization. J Cell Sci 113(Pt 8):1459–1469PubMedGoogle Scholar
  82. 82.
    Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ (2007) Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 117:185–194. doi: 10.1172/JCI28549 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O’Neill LA (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496:238–242. doi: 10.1038/nature11986 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Tripathi C, Tewari BN, Kanchan RK, Baghel KS, Nautiyal N, Shrivastava R, Kaur H, Bhatt ML, Bhadauria S (2014) Macrophages are recruited to hypoxic tumor areas and acquire a pro-angiogenic M2-polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin. Oncotarget 5:5350–5368. doi: 10.18632/oncotarget.2110 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Van den Bossche J, Baardman J, Otto NA, van der Velden S, Neele AE, van den Berg SM, Luque-Martin R, Chen HJ, Boshuizen MC, Ahmed M, Hoeksema MA, de Vos AF, de Winther MP (2016) Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep 17:684–696. doi: 10.1016/j.celrep.2016.09.008 CrossRefPubMedGoogle Scholar
  86. 86.
    Vestweber D (2012) Relevance of endothelial junctions in leukocyte extravasation and vascular permeability. Ann N Y Acad Sci 1257:184–192. doi: 10.1111/j.1749-6632.2012.06558.x CrossRefPubMedGoogle Scholar
  87. 87.
    Vestweber D (2015) How leukocytes cross the vascular endothelium. Nat Rev Immunol 15:692–704. doi: 10.1038/nri3908 CrossRefPubMedGoogle Scholar
  88. 88.
    Wang S, Voisin MB, Larbi KY, Dangerfield J, Scheiermann C, Tran M, Maxwell PH, Sorokin L, Nourshargh S (2006) Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J Exp Med 203:1519–1532. doi: 10.1084/jem.20051210 CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Wee H, Oh HM, Jo JH, Jun CD (2009) ICAM-1/LFA-1 interaction contributes to the induction of endothelial cell-cell separation: implication for enhanced leukocyte diapedesis. Exp Mol Med 41:341–348. doi: 10.3858/emm.2009.41.5.038 CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Perez R, Serneels J, Prenen H, Ghesquiere B, Carmeliet P, Mazzone M (2016) Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–715. doi: 10.1016/j.cmet.2016.09.008 CrossRefPubMedGoogle Scholar
  91. 91.
    Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, Brachvogel B, Hammerschmidt M, Nagy A, Ferrara N, Pasparakis M, Eming SA (2012) CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120:613–625. doi: 10.1182/blood-2012-01-403386 CrossRefPubMedGoogle Scholar
  92. 92.
    Xu Y, An X, Guo X, Habtetsion TG, Wang Y, Xu X, Kandala S, Li Q, Li H, Zhang C, Caldwell RB, Fulton DJ, Su Y, Hoda MN, Zhou G, Wu C, Huo Y (2014) Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol 34:1231–1239. doi: 10.1161/ATVBAHA.113.303041 CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Yeh WL, Lin CJ, Fu WM (2008) Enhancement of glucose transporter expression of brain endothelial cells by vascular endothelial growth factor derived from glioma exposed to hypoxia. Mol Pharmacol 73:170–177. doi: 10.1124/mol.107.038851 CrossRefPubMedGoogle Scholar
  94. 94.
    Yu Y, Sweeney MD, Saad OM, Crown SE, Hsu AR, Handel TM, Leary JA (2005) Chemokine-glycosaminoglycan binding: specificity for CCR2 ligand binding to highly sulfated oligosaccharides using FTICR mass spectrometry. J Biol Chem 280:32200–32208. doi: 10.1074/jbc.M505738200 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research CentreVIB, Campus Gasthuisberg O&N4LeuvenBelgium
  2. 2.Laboratory of Angiogenesis and Vascular Metabolism, Department of OncologyKU Leuven, Campus Gasthuisberg O&N4LeuvenBelgium
  3. 3.Department of Clinical Pathobiochemistry, Faculty of medicineInstitute of Clinical Chemistry and Laboratory MedicineDresdenGermany

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